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Abstract:

The present invention relates to processes and intermediates useful in
the preparation of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) and salts thereof, an
S1P1 receptor modulator that is useful in the treatment of S1P1
receptor-associated disorders, for example, diseases and disorders
mediated by lymphocytes, transplant rejection, autoimmune diseases and
disorders, inflammatory diseases and disorders (e.g., acute and chronic
inflammatory conditions), cancer, and conditions characterized by an
underlying defect in vascular integrity or that are associated with
angiogenesis such as may be pathologic (e.g., as may occur in
inflammation, tumor development and atherosclerosis).
##STR00001##

Claims:

1. A process for preparing an L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia): ##STR00103##
comprising the following steps: a) hydrolyzing a compound of Formula
(IIk): ##STR00104## wherein R3 is C1-C6 alkyl; in the
presence of a lipase and a hydrolyzing-step solvent to form said
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia); and b) contacting said
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid (Formula (Ia)) with L-arginine or a
salt thereof, in the presence of a contacting-step solvent and H2O
to form said L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia).

2. The process according to claim 1, wherein R3 is ethyl.

3. The process according to claim 1, wherein said lipase is immobilized
Candida antarctica lipase B.

5. The process according to claim 1, wherein said hydrolyzing-step
solvent comprises acetonitrile.

6. The process according to claim 1, wherein: said compound of Formula
(IIk) is: ##STR00105## said lipase is immobilized Candida antarctica
lipase B; and said hydrolyzing-step solvent comprises acetonitrile.

7. The process according to claim 1, wherein said hydrolyzing in step a),
is conducted in the presence of a phosphate buffer at a pH of about 7.6
to about 8.0.

8. The process according to claim 7, wherein said phosphate buffer is a
potassium phosphate buffer.

9. The process according to claim 1, wherein said hydrolyzing in step a),
is conducted at a temperature of about 30.degree. C. to about 55.degree.
C.

10. The process according to claim 1, wherein said hydrolyzing in step
a), further comprises the step of isolating said
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid, wherein after said isolating, said
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid has an enantiomeric excess of about 95%
or greater.

12. The process according to claim 1, further comprising the step of
isolating said L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid, wherein after said isolating, said
L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid has a purity of about 95% or greater as
determined by HPLC.

13. The process according to claim 1, further comprising the step of
isolating said L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid, wherein after said isolating, said
L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid has an enantiomeric excess of about 95%
or greater.

14. The process according to claim 1, further comprising the step of
isolating said L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid wherein said L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid is a crystalline form.

15. The process according to claim 14, wherein said crystalline form has
a powder X-ray diffraction (PXRD) pattern substantially as shown in FIG.
5, a differential scanning calorimetry (DSC) trace substantially as shown
in FIG. 6, a thermogravimetric analysis (TGA) profile substantially as
shown in FIG. 7, or a dynamic vapor sorption (DVS) profile substantially
as shown in FIG. 8.

16. An L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid prepared according to claim 1.

17. A pharmaceutical composition comprising an L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid and a pharmaceutically acceptable
carrier, wherein said L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid is prepared according to claim 1.

18. A process of preparing a pharmaceutical composition comprising
admixing an L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid and a pharmaceutically acceptable
carrier, wherein said L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid is prepared according to claim 1.

19. A method for treating an S1P1 receptor-associated disorder in an
individual comprising administering to said individual in need thereof a
therapeutically effective amount of an L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid according to claim 16.

25. A process for preparing
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia): ##STR00106##
comprising the step of hydrolyzing a compound of Formula (IIk):
##STR00107## wherein R3 is C1-C6 alkyl; in the presence
of a lipase and a hydrolyzing-step solvent to form said
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia).

26. The process according to claim 25, wherein R3 is ethyl.

27. The process according to claim 25, wherein said lipase is immobilized
Candida antarctica lipase B.

29. The process according to claim 25, wherein said hydrolyzing-step
solvent comprises acetonitrile.

30. The process according to claim 25, wherein: said compound of Formula
(IIk) is: ##STR00108## said lipase is immobilized Candida antarctica
lipase B; and said hydrolyzing-step solvent comprises acetonitrile.

31. The process according to claim 25, wherein said hydrolyzing is
conducted in the presence of a phosphate buffer at a pH of about 7.6 to
about 8.0.

32. The process according to claim 31, wherein said phosphate buffer is a
potassium phosphate buffer.

33. The process according to claim 25, wherein said hydrolyzing is
conducted at a temperature of about 30.degree. C. to about 55.degree. C.

34. The process according to claim 25, wherein said hydrolyzing further
comprises the step of isolating said
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid, wherein after said isolating, said
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid has an enantiomeric excess of about 95%
or greater.

35. A process for preparing a compound of Formula (IIk): ##STR00109##
wherein R3 is C1-C6 alkyl; comprising the step of
alkylating a compound of Formula (IIj): ##STR00110## with
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula
(IIc)): ##STR00111## in the presence of an alkylating-step base, and an
alkylating-step solvent to form said compound of Formula (IIk), provided
that said alkylating-step solvent is other than a solvent of the group
consisting of dimethylformamide (DMF) and dimethylacetamide (DMA).

40. The process according to claim 35, wherein the molar ratio between
said 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene, said
compound of Formula (IIj) or a salt thereof, and said alkylating-step
base is about 1.0:1.0:1.0 to about 1.2:1.0:1.5.

41. The process according to claim 35, wherein said alkylating is
conducted at a temperature of about 15.degree. C. to about 90.degree. C.

42. A process for preparing a compound of Formula (IIj): ##STR00113##
wherein R3 is C1-C6 alkyl; comprising the step of reducing
a compound of Formula (IIi): ##STR00114## wherein R4, R5, and
R6 are each selected independently from the group consisting of H,
C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4
haloalkyl, C1-C4 haloalkoxy, and nitro; in the presence of a
reducing-step agent, and a reducing-step catalyst, to form said compound
of Formula (IIj).

43. The process according to claim 42, wherein R3 is ethyl.

44. The process according to claim 42, wherein said reducing-step agent
comprises formic acid and a reducing base.

45. The process according to claim 44, wherein said reducing base
comprises triethylamine.

46. The process according to claim 42, wherein said reducing-step
catalyst comprises palladium.

47. The process according to claim 42, wherein said reducing is conducted
in the presence of a reducing-step solvent, wherein said reducing-step
solvent comprises ethyl acetate.

48. The process according to claim 42, wherein the molar ratio between
said compound of Formula (IIi), formic acid, and said reducing base is
about 1.0:2.0:2.0 to about 1.0:4.0:4.0.

49. The process according to claim 42, wherein said reducing is conducted
at a temperature of about 15.degree. C. to about 55.degree. C.

50. A process for preparing a compound of Formula (IIi): ##STR00115##
wherein R3 is C1-C6 alkyl; and R4, R5, and
R6 are each selected independently from the group consisting of H,
C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4
haloalkyl, C1-C4 haloalkoxy, and nitro; comprising the step of
reacting a compound of Formula (IIg): ##STR00116## wherein R1 and
R2 are each independently C1-C6 alkyl, or R1 and
R2 together with the nitrogen atom to which they are both bonded
form a 5-member or 6-member heterocyclic ring; with a compound of Formula
(IIh) or a salt thereof, ##STR00117## wherein R4, R5, and
R6 are each selected independently from the group consisting of H,
C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4
haloalkyl, C1-C4 haloalkoxy, and nitro; in the presence of an
indole-forming acid, to form a compound of Formula (IIi).

51. The process according to claim 50, wherein R1 and R2
together with the nitrogen atom to which they are both bonded form
morpholinyl.

52. The process according to claim 50, wherein R3 is ethyl.

53. The process according to claim 50, wherein R4, R5, and
R6 are each H.

54. The process according to claim 50, wherein said compound of Formula
(IIh) is (4-(benzyloxy)phenyl) hydrazine hydrochloride.

55. The process according to claim 50, wherein said compound of Formula
(IIg) is: ##STR00118##

57. The process according to claim 50, wherein said reacting is conducted
in the presence of a C1-C4 alkylalcohol solvent, wherein said
C1-C4 alkylalcohol solvent comprises ethanol.

58. The process according to claim 50, wherein the molar ratio between
said compound of Formula (IIg) and said compound of Formula (IIh) or a
salt thereof is about 1.0:1.0 to about 1.0:1.3.

59. The process according to claim 50, wherein said reacting is conducted
at a temperature of about 25.degree. C. to about 80.degree. C.

60. A compound of Formula (IIi): ##STR00119## wherein R3 is
C1-C6 alkyl; and R4, R5, and R6 are each
selected independently from the group consisting of H, C1-C4
alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and nitro.

61. A compound according to claim 60, wherein R3 is ethyl, and
R4, R5, and R6 are each H.

Description:

FIELD OF THE INVENTION

[0001] The present invention relates to processes and intermediates useful
in the preparation of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) or salts thereof, an
S1P1 receptor modulator that is useful in the treatment of S1P1
receptor-associated disorders, for example, diseases and disorders
mediated by lymphocytes, transplant rejection, autoimmune diseases and
disorders, inflammatory diseases and disorders (e.g., acute and chronic
inflammatory conditions), cancer, and conditions characterized by an
underlying defect in vascular integrity or that are associated with
angiogenesis such as may be pathologic (e.g., as may occur in
inflammation, tumor development and atherosclerosis).

BACKGROUND OF THE INVENTION

[0002] S1P1 receptor agonists have been shown to possess at least
immunosuppressive, anti-inflammatory, and/or hemostatic activities, e.g.
by virtue of modulating leukocyte trafficking, sequestering lymphocytes
in secondary lymphoid tissues, and/or enhancing vascular integrity.
Accordingly, S1P1 receptor agonists can be useful as immunosuppressive
agents for at least autoimmune diseases and disorders, inflammatory
diseases and disorders (e.g., acute and chronic inflammatory conditions),
transplant rejection, cancer, and/or conditions that have an underlying
defect in vascular integrity or that are associated with angiogenesis
such as may be pathologic (e.g., as may occur in inflammation, tumor
development, and atherosclerosis) with fewer side effects such as the
impairment of immune responses to systemic infection.

[0003] The sphingosine-1-phosphate (SIP) receptors 1-5 constitute a family
of G protein-coupled receptors containing a seven-transmembrane domain.
These receptors, referred to as S1P1 to SIPS (formerly termed endothelial
differentiation gene (EDG) receptor-1, -5, -3, -6, and -8, respectively;
Chun et al., Pharmacological Reviews, 54:265-269, 2002), are activated
via binding by sphingosine-1-phosphate, which is produced by the
sphingosine kinase-catalyzed phosphorylation of sphingosine. S1P1, S1P4,
and SIPS receptors activate Gi but not Gq, whereas S1P2 and S1P3
receptors activate both Gi and Gq. The S1P3 receptor, but not the S1P1
receptor, responds to an agonist with an increase in intracellular
calcium.

[0004] In view of the growing demand for S1P1 agonists useful in the
treatment of S1P1 receptor-associated disorders, the compound
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia):

##STR00002##

has emerged as an important new compound, see PCT patent application,
Serial No. PCT/US2009/004265 hereby incorporated by reference in its
entirety. Accordingly, new and efficient routes leading to
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia), salts, and
intermediates related thereto are needed. The processes and compounds
described herein help meet these and other needs.

SUMMARY OF THE INVENTION

[0005] The processes and intermediates of the present invention are useful
in preparing
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia).
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is useful in the
treatment of S1P1 receptor-associated disorders, such as, psoriasis and
multiple sclerosis, and is disclosed in PCT patent application, Serial
No. PCT/US2009/004265 hereby incorporated by reference in its entirety.

[0006] One aspect of the present invention relates to processes and
intermediates that are useful in preparing the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid, the salt which was found to be
surprisingly and unexpectedly different from what was previously reported
in PCT patent application, Serial No. PCT/US2009/004265.

comprising the following steps: a) cross-coupling bromopentane with a
compound of Formula (IIa):

##STR00004##

[0008] wherein LG1 is selected from the group consisting of Cl, Br,
I, TfO, and TsO, in the presence of:

[0009] i) elemental magnesium;

[0010] ii) an Fe catalyst;

[0011] iii) a cross-coupling-step solvent; and

[0012] iv) a cross-coupling agent;

to form 1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)):

##STR00005##

b) reacting 1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)) with
1,3,5-trioxane in the presence of an acid and a chlorinating agent, to
form 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene of Formula
(IIc):

##STR00006##

c) reacting a compound of Formula (IIg):

##STR00007##

wherein R1 and R2 are each independently C1-C6 alkyl,
or R1 and R2 together with the nitrogen atom to which they are
both bonded form a 5-member or 6-member heterocyclic ring, and R3 is
C1-C6 alkyl;

[0013] with a compound of Formula (IIh) or a salt thereof,

##STR00008##

[0014] wherein R4, R5, and R6 are each selected
independently from the group consisting of H, C1-C4 alkyl,
C1-C4 alkoxy, halogen, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and nitro; in the presence of an
indole-forming acid, to form a compound of Formula (IIi):

##STR00009##

d) reducing the compound of Formula (IIi) in the presence of a
reducing-step agent, and a reducing-step catalyst, to form a compound of
Formula (IIj) or a salt thereof:

##STR00010##

e) alkylating the compound of Formula (IIj) or a salt thereof, with the
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula
(IIc)), in the presence of an alkylating-step base, and an
alkylating-step solvent to form a compound of Formula (IIk):

##STR00011##

f) hydrolyzing the compound of Formula (Ilk) in the presence of a lipase
and a hydrolyzing-step solvent to form
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia):

##STR00012##

g) contacting
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid (Formula (Ia)) with L-arginine or a
salt thereof, in the presence of a contacting-step solvent and H2O
to form the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[13]indol-3-yl)acetic acid of Formula (Ia).

[0015] The present invention further provides processes for preparing an
L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia):

##STR00013##

comprising the following steps: a) hydrolyzing the compound of Formula
(IIk):

##STR00014##

[0016] wherein R3 is C1-C6 alkyl;

in the presence of a lipase and a hydrolyzing-step solvent to form
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia); and b) contacting
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid (Formula (Ia)) with L-arginine or a
salt thereof, in the presence of a contacting-step solvent and H2O
to form the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[1)]indol-3-yl)acetic acid of Formula (Ia).

comprising the step of cross-coupling bromopentane with a compound of
Formula (IIa):

##STR00028##

[0033] wherein LG1 is selected from the group consisting of Cl, Br,
I, TfO, and TsO, in the presence of: [0034] i) elemental magnesium;
[0035] ii) an Fe catalyst; [0036] iii) a cross-coupling-step solvent; and
[0037] iv) a cross-coupling agent; to form
1-cyclopentyl-2-(trifluoromethyl)benzene.

and a pharmaceutically acceptable carrier, wherein
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is prepared according
to any of the processes described herein.

and a pharmaceutically acceptable carrier, wherein
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is prepared according
to any of the processes described herein.

and a pharmaceutically acceptable carrier, wherein the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is prepared according
to any of the processes described herein.

and a pharmaceutically acceptable carrier, wherein the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[1)]indol-3-yl)acetic acid of Formula (Ia) is prepared according
to any of the processes described herein.

[0042] The present invention further provides compounds represented by any
of the formulae described herein.

[0043] The present invention further provides compounds represented by any
of the formulae described herein for use in a process for preparing a
pharmaceutical composition for treating an S1P1 receptor-associated
disorder in an individual.

[0044] The present invention further provides compounds represented by any
of the formulae described herein prepared according to any of the
processes described herein.

[0045] The present invention further provides compounds represented by any
of the formulae described herein prepared according to any of the
processes described herein, for use in a process for preparing a
pharmaceutical composition for treating an S1P1 receptor-associated
disorder in an individual.

[0046] These and other aspects of the invention disclosed herein will be
set forth in greater detail as the patent disclosure proceeds.

[0055] The processes and intermediates of the present invention are useful
in preparing
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[1)]indol-3-yl)acetic acid of Formula (Ia) and salts thereof.
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is useful in the
treatment of S1P1 receptor-associated disorders as described herein and
as described in the PCT patent application, Serial No. PCT/US2009/004265
hereby incorporated by reference in its entirety.

DEFINITIONS

[0056] For clarity and consistency, the following definitions will be used
throughout this patent document.

[0057] The term "C1-C4 alkoxy" is intended to mean a
C1-C4 alkyl radical, as defined herein, attached directly to an
oxygen atom. Some embodiments are 1 to 3 carbons and some embodiments are
1 or 2 carbons. Examples include methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, tert-butoxy, isobutoxy, sec-butoxy and the like.

[0058] The term "C1-C6 alkyl" is intended to mean a straight or
branched carbon radical containing 1 to 6 carbons. Some embodiments are 1
to 5 carbons, some embodiments are 1 to 4 carbons, some embodiments are 1
to 3 carbons and some embodiments are 1 or 2 carbons. Examples of an
alkyl include, but are not limited to, methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl,
tert-pentyl, neo-pentyl, 1-methylbutyl [i.e.,
--CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e.,
--CH2CH(CH3)CH2CH3], n-hexyl and the like.

[0059] The term "C1-C4 haloalkoxy" is intended to mean a
C1-C4 haloalkyl, as defined herein, which is directly attached
to an oxygen atom. Examples include, but are not limited to,
difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,
pentafluoroethoxy and the like.

[0060] The term "C1-C4 haloalkyl" is intended to mean an
C1-C4 alkyl group, defined herein, wherein the alkyl is
substituted with between one halogen up to fully substituted wherein a
fully substituted C1-C6 haloalkyl can be represented by the
formula CnL2n+1 wherein L is a halogen. and "n" is 1, 2, 3, or
4. When more than one halogen is present, the halogens may be the same or
different and selected from the group consisting of fluoro, chloro, bromo
or iodo, preferably fluoro. Some embodiments are 1 to 4 carbons, some
embodiments are 1 to 3 carbons and some embodiments are 1 or 2 carbons.
Examples of haloalkyl groups include, but are not limited to,
fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl,
2,2,2-trifluoroethyl, pentafluoroethyl, and the like.

[0061] The term "halogen" or "halo" is intended to mean a fluoro, chloro,
bromo, or iodo group.

[0062] The term "nitro" is intended to mean a radical of the formula:
--NO2.

[0063] The term "C1-C4 alkylalcohol" is intended to mean a
straight or branched carbon alkane containing 1 to 4 carbons wherein one
hydrogen has been replaced with an OH group. Examples of a
C1-C4 alkylalcohol include, but are not limited to, methanol,
ethanol, isopropanol, n-butanol, tert-butanol, and the like.

[0064] The term "agonists" is intended to mean moieties that interact and
activate a receptor, such as the S1P1 receptor, and initiate a
physiological or pharmacological response characteristic of that
receptor, for example, moieties that activate the intracellular response
upon binding to the receptor, or enhance GTP binding to membranes.

[0065] The term "hydrate" as used herein means a compound, including but
not limited to a pharmaceutically acceptable salt of a compound, that
further includes a stoichiometric or non-stoichiometric amount of water
bound by non-covalent intermolecular forces.

[0066] The term "individual" is intended to mean any animal, including
mammals, preferably mice, rats, other rodents, rabbits, dogs, cats,
swine, cattle, sheep, horses, or primates and most preferably humans.

[0067] The term "pharmaceutical composition" is intended to mean a
composition comprising at least one active ingredient; including but not
limited to Compound of Formula (Ia) and pharmaceutically acceptable
salts, solvates and hydrates thereof, whereby the composition is amenable
to investigation for a specified, efficacious outcome in a mammal (for
example, without limitation, a human). Those of ordinary skill in the art
will understand and appreciate the techniques appropriate for determining
whether an active ingredient has a desired efficacious outcome based upon
the needs of the artisan.

[0068] The term "solvate" as used herein means a compound, including but
not limited to a pharmaceutically acceptable salt of a compound, that
further includes a stoichiometric or non-stoichiometric amount of a
solvent bound by non-covalent intermolecular forces. Preferred solvents
are volatile, non-toxic, and/or acceptable for administration to humans
in trace amounts.

[0069] The term "treatment" or "treating" as used herein includes one or
more of the following:

[0070] (1) prevention of a disease, for example, prevention of a disease,
condition or disorder in an individual that may be predisposed to the
disease, condition or disorder but does not yet experience or display the
pathology or symptomatology of the disease;

[0071] (2) inhibition of a disease, for example, inhibition of a disease,
condition or disorder in an individual that is experiencing or displaying
the pathology or symptomatology of the disease, condition or disorder
(i.e., arresting further development of the pathology and/or
symptomatology); and

[0072] (3) amelioration of a disease, for example, amelioration of a
disease, condition or disorder in an individual that is experiencing or
displaying the pathology or symptomatology of the disease, condition or
disorder (i.e., reversing the pathology and/or symptomatology).

[0073] Whether an individual is in need of treatment is a judgment made by
a caregiver (e.g. nurse practitioner, physician, physician assistant,
nurse, etc. in the case of humans; veterinarian in the case of animals,
including non-human mammals) that an individual or animal requires or
will benefit from treatment. This judgment is made based on a variety of
factors that are in the realm of a caregiver's expertise, but that
includes the knowledge that the individual or animal is ill, or will
become ill, as the result of a disease, condition or disorder that is
treatable by Compound of Formula (Ia) and pharmaceutically acceptable
salts, solvates and hydrates thereof. Accordingly, Compound of Formula
(Ia) and pharmaceutically acceptable salts, solvates and hydrates thereof
can be used in a protective or preventive manner; or Compound of Formula
(Ia) and pharmaceutically acceptable salts, solvates and hydrates thereof
can be used to alleviate, inhibit or ameliorate a disease, condition or
disorder.

[0085] LG1 is selected from the group consisting of Cl, Br, I, TfO,
and TsO;

[0086] R1 and R2 are each independently C1-C6 alkyl,
or R1 and R2 together with the nitrogen atom to which they are
both bonded form a 5-member or 6-member heterocyclic ring;

[0087] R3 is C1-C6 alkyl; and

[0088] R4, R5, and R6 are each selected independently from
the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy,
halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, and
nitro.

[0089] In some embodiments, LG1 is TfO or TsO.

[0090] In some embodiments, LG1 is TfO.

[0091] In some embodiments, LG1 is selected from the group consisting
of Cl, Br, and I.

[0092] In some embodiments, LG1 is Br or I.

[0093] In some embodiments, LG1 is Br.

[0094] In some embodiments, R1 and R2 are each independently
C1-C6 alkyl.

[0095] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form a 5-member or 6-member
heterocyclic ring.

[0096] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form a 6-member heterocyclic ring.

[0097] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form a 5-member heterocyclic ring.

[0098] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form a morpholinyl ring.

[0099] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form a pyrrolidinyl ring.

[0100] In some embodiments, R3 is methyl or ethyl.

[0101] In some embodiments, R3 is ethyl.

[0102] In some embodiments, R4, R5, and R6 are each
selected independently from the group consisting of H, CH3,
OCH3, OCH2CH3, F, Cl, Br, CF3, OCF3, and nitro.

[0103] In some embodiments, R4, R5, and R6 are each
selected independently from the group consisting of H, CH3,
OCH3, OCH2CH3, F, Cl, CF3, OCF3.

[0104] In some embodiments, R4, R5, and R6 are each
selected independently from the group consisting of H and OCH3.

[0105] In some embodiments, R4, R5, and R6 are each H.

[0106] One aspect of the present invention pertains to a compound of
Formula (IIi):

##STR00040##

[0107] wherein: R3 is C1-C6 alkyl. In some embodiments,
R3 is ethyl.

[0108] It is appreciated that certain features of the invention, which
are, for clarity, described in the context of separate embodiments, may
also be provided in combination in a single embodiment. Conversely,
various features of the invention, which are, for brevity, described in
the context of a single embodiment, may also be provided separately or in
any suitable subcombination. All combinations of the embodiments
pertaining to the chemical groups represented by the variables (e.g.,
LG1, R1, R2, R3, R4, R5, and R6)
contained within the generic chemical formulae described herein are
specifically embraced by the present invention just as if each and every
combination was individually explicitly recited, to the extent that such
combinations embrace stable compounds (i.e., compounds that can be
isolated, characterized and tested for biological activity). In addition,
all subcombinations of the chemical groups listed in the embodiments
describing such variables, as well as all subcombinations of uses and
medical indications described herein, are also specifically embraced by
the present invention just as if each and every subcombination of
chemical groups and subcombination of uses and medical indications was
individually and explicitly recited herein.

I. Cross-Coupling Step

[0109] One aspect of the present invention pertains to processes for
preparing 1-cyclopentyl-2-(trifluoromethyl)benzene of Formula (IIb):

##STR00041##

comprising the step of cross-coupling bromopentane with a compound of
Formula (IIa):

##STR00042##

[0110] wherein LG1 is selected from the group consisting of Cl, Br,
I, TfO, and TsO, in the presence of: [0111] i) elemental magnesium;
[0112] ii) an Fe catalyst; [0113] iii) a cross-coupling-step solvent; and
[0114] iv) a cross-coupling agent; to form
1-cyclopentyl-2-(trifluoromethyl)benzene.

[0115] In some embodiments, LG1 is TfO or TsO.

[0116] In some embodiments, LG1 is TfO.

[0117] In some embodiments, LG1 is selected from the group consisting
of Cl, Br, and I.

[0118] In some embodiments, LG1 is Br or I.

[0119] In some embodiments, LG1 is Br.

[0120] In some embodiments, the elemental magnesium is in the form of
magnesium turnings, magnesium ribbons, magnesium powder, or magnesium
rods.

[0121] In some embodiments, the elemental magnesium is in the form of
magnesium turnings.

[0122] In some embodiments, the Fe catalyst is an Fe(III) catalyst (i.e.,
Fe+3).

[0132] In some embodiments, the cross-coupling-step solvent is
substantially free of water.

[0133] In some embodiments, the cross-coupling agent is substantially free
of water.

[0134] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) is conducted under a substantially inert
atmosphere.

[0135] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) is conducted under a substantially inert
atmosphere comprising argon or nitrogen.

[0136] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) is conducted under a substantially inert
atmosphere comprising nitrogen.

[0137] In some embodiments, the molar ratio between bromopentane and the
compound of Formula (IIa) is about 1.0:1.0 to about 10.0:1.0.

[0138] In some embodiments, the molar ratio between bromopentane and the
compound of Formula (IIa) is about 1.0:1.0 to about 5.0:1.0.

[0139] In some embodiments, the molar ratio between bromopentane and the
compound of Formula (IIa) is about 1.0:1.0 to about 2.0:1.0.

[0140] In some embodiments, the molar ratio between bromopentane and the
compound of Formula (IIa) is about 1.2:1.0.

[0141] In some embodiments, the molar ratio between the compound of
Formula (IIa) and the Fe catalyst is about 1.0:0.01 to about 1.0:1.0.

[0142] In some embodiments, the molar ratio between the compound of
Formula (IIa) and the Fe catalyst is about 1.0:0.05 to about 1.0:0.5.

[0143] In some embodiments, the molar ratio between the compound of
Formula (IIa) and the Fe catalyst is about 1.0:0.10 to about 1.0:0.3.

[0144] In some embodiments, the molar ratio between the compound of
Formula (IIa) and the Fe catalyst is about 1.0:0.15.

[0145] In some embodiments, the molar ratio between the compound of
Formula (IIa) and the elemental magnesium is about 1.0:1.0 to about
1.0:5.0.

[0146] In some embodiments, the molar ratio between the compound of
Formula (IIa) and the elemental magnesium is about 1.0:1.0 to about
1.0:3.0.

[0147] In some embodiments, the molar ratio between the compound of
Formula (IIa) and the elemental magnesium is about 1.0:1.0 to about
1.0:2.5.

[0148] In some embodiments, the molar ratio between the compound of
Formula (IIa) and the elemental magnesium is about 1.0:1.5.

[0149] In some embodiments, the molar ratio between bromopentane, the
compound of Formula (IIa), the elemental magnesium, and the Fe catalyst
is about 1.2:1.0:1.5:0.15.

[0150] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) is conducted at a temperature of about
0° C. to about 75° C.

[0151] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) is conducted at a temperature of about
10° C. to about 55° C.

[0152] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) is conducted at a temperature of about
10° C. to about 45° C.

[0153] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) is conducted by adding the cross-coupling agent
to a mixture comprising the elemental magnesium, the Fe catalyst, and the
cross-coupling-step solvent to form a first cross-coupling mixture.

[0154] In some embodiments, adding the cross-coupling agent to a mixture
comprising the elemental magnesium, the Fe catalyst, and the
cross-coupling-step solvent is conducted at a rate so the internal
temperature during the addition of the cross-coupling agent to the
mixture comprising the elemental magnesium, the Fe catalyst, and the
cross-coupling-step solvent is maintained at about 0° C. to about
45° C.

[0155] In some embodiments, adding the cross-coupling agent to a mixture
comprising the elemental magnesium, the Fe catalyst, and the
cross-coupling-step solvent is conducted at a rate so the internal
temperature during the addition of the cross-coupling agent to the
mixture comprising the elemental magnesium, the Fe catalyst, and the
cross-coupling-step solvent is maintained at about 10° C. to about
30° C.

[0156] In some embodiments, adding the cross-coupling agent to a mixture
comprising the elemental magnesium, the Fe catalyst, and the
cross-coupling-step solvent is conducted at a rate so the internal
temperature during the addition of the cross-coupling agent to the
mixture comprising the elemental magnesium, the Fe catalyst, and the
cross-coupling-step solvent is maintained at about 15° C. to about
25° C.

[0157] In some embodiments, the first cross-coupling mixture is maintained
at a temperature of about 10° C. to about 55° C.

[0158] In some embodiments, the first cross-coupling mixture is maintained
at a temperature of about 20° C. to about 50° C.

[0159] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) further comprises the step of adding a mixture
comprising the bromopentane and the compound of Formula (IIa) to the
first cross-coupling mixture to form a second cross-coupling mixture.

[0160] In some embodiments, adding the mixture comprising the bromopentane
and the compound of Formula (IIa) to the first cross-coupling mixture is
conducted at a rate so the internal temperature during the addition of
the mixture comprising the bromopentane and the compound of Formula (IIa)
to the first cross-coupling mixture is maintained at about 20° C.
to about 35° C.

[0161] In some embodiments, the mixture comprising the bromopentane and
the compound of Formula (IIa) to the first cross-coupling mixture is
conducted at a rate so the internal temperature during the addition of
the mixture comprising the bromopentane and the compound of Formula (IIa)
to the first cross-coupling mixture is maintained at about 25° C.
to about 30° C.

[0162] In some embodiments, the second cross-coupling mixture is
maintained at a temperature of about 20° C. to about 35° C.

[0163] In some embodiments, the second cross-coupling mixture is
maintained at a temperature of about 20° C. to about 30° C.

[0164] In some embodiments, the second cross-coupling mixture is
maintained at a temperature of about 23° C. to about 27° C.

[0165] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) further comprises the step of quenching the
second cross-coupling mixture with aqueous HCl.

[0166] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) is conducted wherein: [0167] the compound of
Formula (IIa) is:

[0167] ##STR00044## [0168] the elemental magnesium is in the form of
magnesium turnings; [0169] the Fe catalyst is FeCl3; [0170] the
cross-coupling-step solvent comprises tetrahydrofuran (THF); and [0171]
the cross-coupling agent comprises N,N,N',N'-tetramethylethylenediamine
(TMEDA).

[0172] In some embodiments, the molar ratio between bromopentane and the
compound of Formula (IIa) is about 1.0:1.0 to about 2.0:1.0.

[0173] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) is performed wherein the molar ratio between
the compound of Formula (IIa) and the Fe catalyst is about 1.0:0.10 to
about 1.0:0.3.

[0174] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) is performed wherein the molar ratio between
the compound of Formula (IIa) and the elemental magnesium is about
1.0:1.0 to about 1.0:2.5.

[0175] In some embodiments, the step of cross-coupling bromopentane with a
compound of Formula (IIa) is performed wherein: [0176] the compound of
Formula (IIa) is:

[0176] ##STR00045## [0177] the elemental magnesium is in the form of
magnesium turnings; [0178] the Fe catalyst is FeCl3; [0179] the
cross-coupling-step solvent comprises tetrahydrofuran (THF); and [0180]
the cross-coupling agent comprises N,N,N',N'-tetramethylethylenediamine
(TMEDA); and

[0181] wherein: [0182] the molar ratio between bromopentane and the
compound of Formula (IIa) is about 1.0:1.0 to about 2.0:1.0; [0183] the
molar ratio between the compound of Formula (IIa) and the Fe catalyst is
about 1.0:0.10 to about 1.0:0.3; and [0184] the molar ratio between the
compound of Formula (IIa) and the elemental magnesium is about 1.0:1.0 to
about 1.0:2.5.

II. Chloromethylation Step

[0185] One aspect of the present invention pertains to processes for
preparing 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene of
Formula (IIc):

[0190] In some embodiments, the chlorinating agent comprises
chlorosulfonic acid.

[0191] In some embodiments, the chlorinating agent comprises thionyl
chloride.

[0192] In some embodiments, the step of reacting
1-cyclopentyl-2-(trifluoromethyl)benzene

[0193] (Formula IIb) with 1,3,5-trioxane in the presence of an acid and a
chlorinating agent is conducted in the presence of a suitable solvent.

[0194] In some embodiments, the step of reacting
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula IIb) with
1,3,5-trioxane in the presence of an acid and a chlorinating agent is
conducted under a substantially inert atmosphere.

[0195] In some embodiments, the step of reacting
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula IIb) with
1,3,5-trioxane in the presence of an acid and a chlorinating agent is
conducted under a substantially inert atmosphere comprising argon or
nitrogen.

[0196] In some embodiments, the step of reacting
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula IIb) with
1,3,5-trioxane in the presence of an'acid and a chlorinating agent is
conducted under an atmosphere comprising substantially nitrogen.

[0197] In some embodiments, the molar ratio between the
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)), the
1,3,5-trioxane, and the chlorinating agent is about 1.0:0.3:1.0 to about
1.0:3.0:3.0.

[0198] In some embodiments, the molar ratio between the
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)), the
1,3,5-trioxane, and the chlorinating agent is about 1.0:1.0:1.5 to about
1.0:2.0:2.5.

[0199] In some embodiments, the molar ratio between the
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)), the
1,3,5-trioxane, and the chlorinating agent is about 1.0:1.5:2.0.

[0200] In some embodiments, the molar ratio between the
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)), the
1,3,5-trioxane, the chlorinating agent, and the acid is about
1.0:1.5:2.0:8.0.

[0201] In some embodiments, the step of reacting
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula IIb) with
1,3,5-trioxane in the presence of an acid and a chlorinating agent is
conducted at a temperature of about -15° C. to about 35° C.

[0202] In some embodiments, the step of reacting
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula IIb) with
1,3,5-trioxane in the presence of an acid and a chlorinating agent is
conducted at a temperature of about -10° C. to about 25° C.

[0203] In some embodiments, the step of reacting
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula IIb) with
1,3,5-trioxane in the presence of an acid and a chlorinating agent is
conducted at a temperature of about -5° C. to about 15° C.

[0204] In some embodiments, the step of reacting
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)) with
1,3,5-trioxane in the presence of an acid and a chlorinating agent,
further comprises the step of adding the
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)) to a mixture
comprising the acid, the chlorinating agent and the 1,3,5-trioxane.

[0205] In some embodiments, the adding the
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)) to the mixture
comprising the acid, the chlorinating agent, and the 1,3,5-trioxane is
conducted at a rate so the internal temperature during the addition of
the 1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)) to the
mixture comprising the acid, the chlorinating agent, and the
1,3,5-trioxane is maintained at about -25° C. to about 15°
C.

[0206] In some embodiments, the adding the
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)) to the mixture
comprising the acid, the chlorinating agent, and the 1,3,5-trioxane is
conducted at a rate so the internal temperature during the addition of
the 1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)) to the
mixture comprising the acid, the chlorinating agent, and the
1,3,5-trioxane is maintained at about -15° C. to about 10°
C.

[0207] In some embodiments, the adding the
1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)) to the mixture
comprising the acid, the chlorinating agent, and the 1,3,5-trioxane is
conducted at a rate so the internal temperature during the addition of
the 1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIb)) to the
mixture comprising the acid, the chlorinating agent, and the
1,3,5-trioxane is maintained at about -10° C. to about 0°
C.

[0208] In some embodiments, [0209] the acid comprises sulfuric acid; and
[0210] the chlorinating agent comprises thionyl chloride. III. Indole
Forming Step One aspect of the present invention pertains to processes
for preparing a compound of Formula (IIi):

##STR00048##

[0211] wherein R3 is C1-C6 alkyl; and R4, R5, and
R6 are each selected independently from the group consisting of H,
C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4
haloalkyl, C1-C4 haloalkoxy, and nitro;

[0212] comprising the step of reacting a compound of Formula (IIg):

##STR00049##

wherein R1 and R2 are each independently C1-C6 alkyl,
or R1 and R2 together with the nitrogen atom to which they are
both bonded form a 5-member or 6-member heterocyclic ring;

[0213] with a compound of Formula (IIh) or a salt thereof,

##STR00050##

[0214] in the presence of an indole-forming acid, to form a compound of
Formula (IIi).

[0215] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid, optionally comprises a drying agent.

[0216] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid, comprises a drying agent.

[0217] In some embodiments, the drying agent is selected from the group of
magnesium sulfate, sodium sulfate, and molecular sieves.

[0218] In some embodiments, the drying agent is magnesium sulfate.

[0219] In some embodiments, the drying agent is sodium sulfate.

[0220] In some embodiments, the drying agent is molecular sieves.

[0221] In some embodiments, R1 and R2 are each independently
C1-C6 alkyl.

[0222] In some embodiments, R1 and R2 are each independently
methyl or ethyl.

[0223] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form a 5-member or 6-member
heterocyclic ring.

[0224] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form a 5-member heterocyclic ring.

[0225] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form pyrrolidinyl.

[0226] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form a 6-member heterocyclic ring.

[0227] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form piperidinyl or morpholinyl.

[0228] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form piperidinyl.

[0229] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form morpholinyl.

[0230] In some embodiments, R3 is methyl or ethyl.

[0231] In some embodiments, R3 is ethyl.

[0232] In some embodiments, R4, R5, and R6 are each
selected independently from the group consisting of H, CH3,
OCH3, OCH2CH3, F, Cl, Br, CF3, OCF3, and nitro.

[0233] In some embodiments, R4, R5, and R6 are each
selected independently from the group consisting of H, CH3,
OCH3, OCH2CH3, F, Cl, CF3, OCF3.

[0234] In some embodiments, R4, R5, and R6 are each
selected independently from the group consisting of H and OCH3.

[0235] In some embodiments, R4, R5, and R6 are each H.

[0236] In some embodiments, the compound of Formula (IIi) is:

##STR00051##

[0237] In some embodiments, the compound of Formula (IIi) is:

##STR00052##

[0238] In some embodiments, the compound of Formula (IIg) is:

##STR00053##

[0239] In some embodiments, the compound of Formula (IIh) is
(4-(benzyloxy)phenyl) hydrazine:

##STR00054##

or a salt thereof.

[0240] In some embodiments, the compound of Formula (IIh) is
(4-(benzyloxy)phenyl) hydrazine hydrochloride.

[0241] In some embodiments, the indole-forming acid comprises a Brcnsted
acid or a Lewis acid.

[0250] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid is conducted in the presence of a suitable
solvent.

[0251] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid is conducted in the presence of a protic
solvent, a halogenated solvent, an ether solvent, or an aprotic solvent.

[0252] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid is conducted in the presence of a protic
solvent.

[0253] In some embodiments, the protic solvent comprises a C1-C4
alkylalcohol solvent.

[0254] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid is conducted in the presence of a halogenated
solvent.

[0255] In some embodiments, the halogenated solvent comprises
dichloromethane.

[0256] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid is conducted in the presence of an ether
solvent.

[0257] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid is conducted in the presence of an aprotic
solvent.

[0258] In some embodiments, the aprotic solvent comprises acetonitrile or
toluene.

[0259] In some embodiments, the aprotic solvent comprises acetonitrile.

[0260] In some embodiments, the aprotic solvent comprises toluene.

[0261] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid is conducted in the presence of a
C1-C4 alkylalcohol solvent.

[0262] In some embodiments, the C1-C4 alkylalcohol solvent
comprises methanol or ethanol.

[0263] In some embodiments, the C1-C1 alkylalcohol solvent
comprises ethanol.

[0264] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid is conducted under a substantially inert
atmosphere.

[0265] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid is conducted under a substantially inert
atmosphere comprising argon or nitrogen.

[0266] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid is conducted under a substantially inert
atmosphere comprising nitrogen.

[0267] In some embodiments, the molar ratio between the compound of
Formula (IIg) and the compound of Formula (IIh) or a salt thereof is
about 1.0:1.0 to about 1.0:2.0.

[0268] In some embodiments, the molar ratio between the compound of
Formula (IIg) and the compound of Formula (IIh) or a salt thereof is
about 1.0:1.0 to about 1.0:1.5.

[0269] In some embodiments, the molar ratio between the compound of
Formula (IIg) and the compound of Formula (IIh) or a salt thereof is
about 1.0:1.0 to about 1.0:1.3.

[0270] In some embodiments, the molar ratio between the compound of
Formula (IIg) and the compound of Formula (IIh) or a salt thereof is
about 1.0:1.0 to about 1.0:1.1.

[0271] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid, is conducted at a temperature of about
25° C. to about 80° C.

[0272] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid, is conducted at a temperature of about
50° C. to about 70° C.

[0273] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid, is conducted at a temperature of about
60° C. to about 65° C.

[0274] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid comprises formation of an imine intermediate of
Formula (III):

##STR00055##

[0275] In some embodiments, R3 is ethyl.

[0276] In some embodiments, R4, R5, and R6 are each H.

[0277] In some embodiments, R3 is ethyl, and R4, R5, and
R6 are each H.

[0278] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid comprises formation of an imine intermediate of
the formula:

##STR00056##

[0279] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid, is continued until about 8.0% or less of the
compound of Formula (III) is present as determined by HPLC.

[0280] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid, is continued until about 6.0% or less of the
compound of Formula (III) is present as determined by HPLC.

[0281] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid, is continued until about 5.0% or less of the
compound of Formula (III) is present as determined by HPLC.

[0282] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid, is continued until about 4.0% or less of the
compound of Formula (III) is present as determined by HPLC.

[0283] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid, further comprises the steps of isomerizing and
crystallizing the compound of Formula (IIi) at a temperature of about
20° C. to about 25° C. to form a suspension comprising said
compound of Formula (IIi).

[0284] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid, further comprises the step of cooling said
suspension comprising said compound of Formula (IIi) to a temperature of
about 0° C. to about 5° C.

[0285] In some embodiments, the step of reacting a compound of Formula
(IIg) with a compound of Formula (IIh) or a salt thereof, in the presence
of an indole-forming acid, further comprises the step of isolating the
compound of Formula (In). In some embodiments, isolating the compound of
Formula (IIi) is conducted by filtration.

IV. Processes for Preparing Compounds of Formula (IIg)

[0286] One aspect of the present invention pertains to processes for
preparing a compound of Formula (IIg):

##STR00057##

[0287] wherein R3 is C1-C6 alkyl;

comprising the following steps of: a) reacting cyclopentanone with a
secondary amine of Formula (IId):

##STR00058##

[0288] wherein R1 and R2 are each independently C1-C6
alkyl, or R1 and R2 together with the nitrogen atom to which
they are both bonded form a 5-member or 6-member heterocyclic ring; to
form a compound of Formula (IIe):

##STR00059##

and b) reacting the compound of Formula (IIe) with a compound of Formula
(IIf):

##STR00060##

[0289] wherein R3 is C1-C6 alkyl,

to form the compound of Formula (IIg).

[0290] IVa. Enamine Formation, Step a)

[0291] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form a 5-member or 6-member
heterocyclic ring.

[0292] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form a 5-member heterocyclic ring.

[0293] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form pyrrolidinyl.

[0294] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form a 6-member heterocyclic ring.

[0295] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form piperidinyl or morpholinyl.

[0296] In some embodiments, R1 and R2 together with the nitrogen
atom to which they are both bonded form morpholinyl.

[0297] In some embodiments, the compound of Formula (IIe) is:

##STR00061##

[0298] In some embodiments, the step of reacting cyclopentanone with a
secondary amine of Formula (IId) is conducted in the presence of an
azeotropic solvent.

[0299] In some embodiments, the azeotropic solvent comprises benzene,
toluene, cyclohexane or anisole.

[0300] In some embodiments, the azeotropic solvent comprises cyclohexane.

[0301] In some embodiments, the step of reacting cyclopentanone with a
secondary amine of Formula (IId) is conducted under a substantially inert
atmosphere.

[0302] In some embodiments, the step of reacting cyclopentanone with a
secondary amine of Formula (Id) is conducted under an atmosphere
comprising argon or nitrogen.

[0303] In some embodiments, the step of reacting cyclopentanone with a
secondary amine of Formula (IId) is conducted under an atmosphere
comprising nitrogen.

[0304] In some embodiments, the molar ratio of cyclopentanone and the
secondary amine of Formula (IId) is about 1.0:1.0 to about 1.0:2.0.

[0305] In some embodiments, the molar ratio of cyclopentanone and the
secondary amine of Formula (IId) is about 1.0:1.0 to about 1.0:1.5.

[0306] In some embodiments, the molar ratio of cyclopentanone and the
secondary amine of Formula (IId) is about 1.0:1.0 to about 1.0:1.2.

[0307] In some embodiments, the molar ratio of cyclopentanone and the
secondary amine of Formula (IId) is about 1.0:1.0 to about 1.0:1.05.

[0308] In some embodiments, the molar ratio of cyclopentanone and the
secondary amine of Formula (IId) is about 1.0:1.0 to about 1.0:1.005.

[0309] In some embodiments, the step of reacting cyclopentanone with a
secondary amine of Formula (IId) is conducted at a temperature of about
60° C. to about 155° C.

[0310] In some embodiments, the step of reacting cyclopentanone with a
secondary amine of Formula (IId) is conducted at a temperature of about
65° C. to about 111° C.

[0311] In some embodiments, the step of reacting cyclopentanone with a
secondary amine of Formula (IId) is conducted at a temperature of about
85° C. to about 95° C.

[0312] In some embodiments, the step of reacting cyclopentanone with a
secondary amine of Formula (IId) further comprises a step of removing
water.

[0313] In some embodiments, the step of reacting cyclopentanone with a
secondary amine of Formula (IId) further comprises a step of removing
water via a Dean-Stark water trap.

[0314] In some embodiments, the removing water step is conducted until
about 10% or less of cyclopentanone is present as determined by gas
chromatography.

[0315] In some embodiments, the removing water step is conducted until
about 6% or less of cyclopentanone is present as determined by gas
chromatography.

[0316] In some embodiments, the removing water step is conducted until
about 3% or less of cyclopentanone is present as determined by gas
chromatography.

[0317] In some embodiments, the removing water is conducted until about
10% or less of the secondary amine of Formula (IId) is present as
determined by gas chromatography.

[0318] In some embodiments, the removing water is conducted until about 6%
or less of the secondary amine of Formula (IId) is present as determined
by gas chromatography.

[0319] In some embodiments, the removing water is conducted until about 3%
or less of the secondary amine of Formula (IId) is present as determined
by gas chromatography.

[0320] IVa. Reacting the enamine of formula (IIe) with a compound of
formula (IIf), Step b)

[0321] In some embodiments, the step of reacting the compound of Formula
(IIe) with a compound of Formula (IIf) is conducted in the presence of an
azeotropic solvent.

[0322] In some embodiments, the azeotropic solvent comprises benzene,
toluene, cyclohexane or anisole.

[0323] In some embodiments, the azeotropic solvent comprises cyclohexane.

[0324] In some embodiments, the step of reacting the compound of Formula
(IIe) with a compound of Formula (IIf) is conducted under a substantially
inert atmosphere.

[0325] In some embodiments, the step of reacting the compound of Formula
(IIe) with a compound of Formula (IIf) is conducted under an atmosphere
comprising argon or nitrogen.

[0326] In some embodiments, the step of reacting the compound of Formula
(IIe) with a compound of Formula (IIf)) is conducted under an atmosphere
comprising nitrogen.

[0327] In some embodiments, the molar ratio between the compound of
Formula (IIe) and the compound of Formula (IIf)) is about 1.0:1.0 to
about 1.0:2.0.

[0328] In some embodiments, the molar ratio between the compound of
Formula (IIe) and the compound of Formula (IIf) is about 1.0:1.0 to about
1.0:1.8.

[0329] In some embodiments, the molar ratio between the compound of
Formula (IIe) and the compound of Formula (IIf) is about 1.0:1.0 to about
1.0:1.4.

[0330] In some embodiments, the molar ratio between the compound of
Formula (IIe) and the compound of Formula (IIf) is about 1.0:1.0 to about
1.0:1.2.

[0331] In some embodiments, the molar ratio between the compound of
Formula (IIe) and the compound of Formula (IIf) is about 1.0:1.1.

[0332] In some embodiments, the step of reacting the compound of Formula
(IIe) with a compound of Formula (IIf) is conducted at a temperature of
about 25° C. to about 105° C.

[0333] In some embodiments, the step of reacting the compound of Formula
(IIe) with a compound of Formula (IIf) is conducted at a temperature of
about 55° C. to about 100° C.

[0334] In some embodiments, the step of reacting the compound of Formula
(IIe) with a compound of Formula (IIf) is conducted at a temperature of
about 60° C. to about 95° C.

[0335] In some embodiments, the step of reacting the compound of Formula
(IIe) with a compound of Formula (IIf) further comprises a step of
removing water.

[0336] In some embodiments, the step of reacting the compound of Formula
(IIe) with a compound of Formula (IIf) further comprises a step of
removing water via a Dean-Stark water trap.

[0337] In some embodiments, removing water step is continued until about
5.0% or less of the compound of Formula (IIe) is present as determined by
gas chromatography.

[0338] In some embodiments, removing water step is continued until about
2.5% or less of the compound of Formula (IIe) is present as determined by
gas chromatography.

[0339] In some embodiments, removing water step is continued until about
2.0% or less of the compound of Formula (IIe) is present as determined by
gas chromatography.

[0340] In some embodiments, removing water step is continued until about
1.0% or less of the compound of Formula (IIe) is present as determined by
gas chromatography.

[0341] In some embodiments, removing water step is continued until about
0.5% or less of the compound of Formula (IIe) is present as determined by
gas chromatography.

V. Reduction Step

[0342] One aspect of the present invention pertains to processes for
preparing a compound of Formula (IIj) or a salt thereof:

##STR00062##

[0343] wherein R3 is C1-C6 alkyl;

comprising the step of reducing a compound of Formula (IIi):

##STR00063##

wherein R4, R5, and R6 are each selected independently
from the group consisting of H, C1-C4 alkyl, C1-C4
alkoxy, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy,
and nitro;

[0344] in the presence of a reducing-step agent, and a reducing-step
catalyst, to form the compound of Formula (IIj).

[0345] In some embodiments, the compound of Formula (IIj) is:

##STR00064##

or a salt thereof.

[0346] In some embodiments, R3 is methyl or ethyl.

[0347] In some embodiments, R3 is ethyl.

[0348] In some embodiments, the reducing-step agent comprises formic acid
and a reducing base.

[0349] In some embodiments, the reducing base comprises an inorganic base.

[0350] In some embodiments, the reducing base comprises a carbonate base.

[0356] In some embodiments, the reducing base comprises triethylamine.

[0357] In some embodiments, the reducing-step catalyst comprises
palladium.

[0358] In some embodiments, the reducing-step catalyst comprises palladium
on carbon.

[0359] In some embodiments, the reducing-step catalyst comprises about 2%
palladium on carbon to about 10% palladium on carbon.

[0360] In some embodiments, the reducing-step catalyst comprises about 10%
palladium on carbon.

[0361] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted in the presence of a suitable solvent.

[0362] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted in the presence of a reducing-step solvent.

[0363] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted in the presence of a reducing-step solvent
comprising a C1-C4 alkylalcohol.

[0364] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted in the presence of a reducing-step solvent
comprising methanol or ethanol.

[0365] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted in the presence of a reducing-step solvent
comprising ethyl acetate.

[0366] In some embodiments, the ethyl acetate is substantially free of
dissolved oxygen.

[0367] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted under a substantially inert atmosphere.

[0368] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted under a substantially inert atmosphere comprising
argon or nitrogen.

[0369] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted under a substantially inert atmosphere comprising
nitrogen.

[0370] In some embodiments, the molar ratio between the compound of
Formula (IIi), formic acid, and the reducing base is about 1.0:1.0:1.0 to
about 1.0:6.0:6.0.

[0371] In some embodiments, the molar ratio between the compound of
Formula (IIi), formic acid, and the reducing base is about 1.0:1.0:1.0 to
about 1.0:5.0:5.0.

[0372] In some embodiments, the molar ratio between the compound of
Formula (IIi), formic acid, and the reducing base is about 1.0:2.0:2.0 to
about 1.0:4.0:4.0.

[0373] In some embodiments, the molar ratio between the compound of
Formula (IIi), formic acid, and the reducing base is about 1.0:2.0:2.0 to
about 1.0:3.0:3.0.

[0374] In some embodiments, the molar ratio between the compound of
Formula (IIi), formic acid, and the reducing base is about 1.0:3.0:3.0.

[0375] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted at a temperature of about 15° C. to about
55° C.

[0376] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted at a temperature of about 20° C. to about
45° C.

[0377] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted at a temperature of about 25° C. to about
35° C.

[0378] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted by adding the reducing base to a mixture comprising
the compound of Formula (IIi), formic acid, the reducing-step catalyst,
and the reducing-step solvent.

[0379] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst is conducted by adding triethylamine to a mixture comprising the
compound of Formula (IIi), formic acid, the reducing-step catalyst, and
the reducing-step solvent at a temperature of about 25° C. to
about 35° C., wherein the compound of Formula (IIi) is:

##STR00065##

[0380] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst, further comprises the step of crystallizing the compound of
Formula (IIj) in the presence of ethyl acetate and heptanes.

[0381] In some embodiments, crystallizing the compound of Formula (IIj) is
conducted at a temperature of about 0° C. to about 20° C.

[0382] In some embodiments, crystallizing the compound of Formula (IIj) is
conducted at a temperature of about 5° C. to about 15° C.

[0383] In some embodiments, crystallizing the compound of Formula (IIj) is
conducted at a temperature of about 10° C.

[0384] In some embodiments, the step of reducing a compound of Formula
(IIi) in the presence of a reducing-step agent, and a reducing-step
catalyst, further comprises the step of isolating the compound of Formula
(IIj).

[0385] In some embodiments, isolating the compound of Formula (IIj) is
conducted by filtration.

VI. Alkylating Step

[0386] One aspect of the present invention pertains to processes for
preparing a compound of Formula (Ilk):

##STR00066##

[0387] wherein R3 is C1-C6 alkyl;

comprising the step of alkylating a compound of Formula (IIj) or a salt
thereof:

in the presence of an alkylating-step base, and an alkylating-step
solvent to form the compound of Formula (IIk).

[0388] In some embodiments, the alkylating-step solvent is other than
dimethylformamide (DMF). In some embodiments, the alkylating-step solvent
is other than dimethylacetamide (DMA). In some embodiments, the
alkylating-step solvent is other than a solvent of the group consisting
of dimethylformamide (DMF) and dimethylacetamide (DMA).

[0389] In some embodiments, the compound of Formula (Ilk) is:

##STR00069##

[0390] In some embodiments, R3 is methyl or ethyl.

[0391] In some embodiments, R3 is ethyl.

[0392] In some embodiments, the alkylating-step base is an inorganic base.

[0393] In some embodiments, the alkylating-step base comprises a carbonate
base.

[0399] In some embodiments, the alkylating-step solvent comprises
acetonitrile.

[0400] In some embodiments, the alkylating-step solvent is substantially
free of water.

[0401] In some embodiments, the step of alkylating a compound of Formula
(IIj) or a salt thereof, with
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
in the presence of an alkylating-step base, and an alkylating-step
solvent, is conducted wherein:

[0402] the compound of Formula (IIj) is:

##STR00070##

or a salt thereof;

[0403] the alkylating-step base comprises cesium carbonate; and

[0404] the alkylating-step solvent comprises acetonitrile.

[0405] In some embodiments, the step of alkylating a compound of Formula
(IIj) or a salt thereof, with
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
in the presence of an alkylating-step base, and an alkylating-step
solvent is conducted under a substantially inert atmosphere.

[0406] In some embodiments, the step of alkylating a compound of Formula
(IIj) or a salt thereof, with
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
in the presence of an alkylating-step base, and an alkylating-step
solvent is conducted under a substantially inert atmosphere comprising
argon or nitrogen.

[0407] In some embodiments, the step of alkylating a compound of Formula
(IIj) or a salt thereof, with
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
in the presence of an alkylating-step base, and an alkylating-step
solvent is conducted under a substantially inert atmosphere comprising
nitrogen.

[0408] In some embodiments, the molar ratio between
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula
(IIc)), the compound of Formula (IIj) or a salt thereof, and the
alkylating-step base is about 1.0:1.0:0.5 to about 2.0:1.0:3.0.

[0409] In some embodiments, the molar ratio between
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula
(IIc)), the compound of Formula (IIj) or a salt thereof, and the
alkylating-step base is about 1.0:1.0:1.0 to about 1.5:1.0:2.0.

[0410] In some embodiments, the molar ratio between
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula
(IIc)), the compound of Formula (IIj) or a salt thereof, and the
alkylating-step base is about 1.0:1.0:1.0 to about 1.2:1.0:1.5.

[0411] In some embodiments, the molar ratio between
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula
(IIc)), the compound of Formula (IIj) or a salt thereof, and the
alkylating-step base is about 1.1:1.0:1.3

[0412] In some embodiments, the step of alkylating a compound of Formula
(IIj) or a salt thereof, with
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
in the presence of an alkylating-step base, and an alkylating-step
solvent is conducted at a temperature of about 15° C. to about
90° C.

[0413] In some embodiments, the step of alkylating a compound of Formula
(IIIj) or a salt thereof, with
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
in the presence of an alkylating-step base, and an alkylating-step
solvent is conducted at a temperature of about 21° C. to about
85° C.

[0414] In some embodiments, the step of alkylating a compound of Formula
(IIj) or a salt thereof, with
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
in the presence of an alkylating-step base, and an alkylating-step
solvent is conducted at a temperature of about 65° C. to about
80° C.

[0415] In some embodiments, the step of alkylating a compound of Formula
(IIj) or a salt thereof, with
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
in the presence of an alkylating-step base, and an alkylating-step
solvent, further comprises the step of adding
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
to a mixture comprising the compound of Formula (IIj) or a salt thereof,
alkylating-step base, and alkylating-step solvent to form an alkylating
mixture.

[0416] In some embodiments, adding
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
to the mixture comprising the compound of Formula (IIj) or a salt
thereof, alkylating-step base, and alkylating-step solvent is conducted
with heating so the internal temperature during the addition of
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
to the alkylating mixture comprising the compound of Formula (IIj) or a
salt thereof, alkylating-step base, and alkylating-step solvent is about
20° C. to about 85° C.

[0417] In some embodiments, the alkylating mixture is maintained at about
60° C. to about 85° C.

[0418] In some embodiments, the alkylating mixture is maintained at about
70° C. to about 85° C.

[0419] In some embodiments, the alkylating mixture is maintained at about
75° C. to about 80° C.

[0420] In some embodiments, the step of alkylating a compound of Formula
(IIj) or a salt thereof, with
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
in the presence of an alkylating-step base, and an alkylating-step
solvent, further comprises the steps of cooling the alkylating mixture to
a temperature of about 50° C. to about 60° C. and filtering
the alkylating mixture to form a filtered mixture.

[0421] In some embodiments, the step of alkylating a compound of Formula
(IIj) or a salt thereof, with
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
in the presence of an alkylating-step base, and an alkylating-step
solvent, further comprises the step of precipitating the compound of
Formula (IIk) from the filtered mixture.

[0422] In some embodiments, precipitating the compound of Formula (IIk)
from the filtered mixture comprises reducing the volume of the filtered
mixture.

[0423] In some embodiments, precipitating the compound of Formula (IIk)
from the filtered mixture comprises reducing the volume of the filtered
mixture by about one half.

[0424] In some embodiments, the step of alkylating a compound of Formula
(IIj) or a salt thereof, with
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula (IIc))
in the presence of an alkylating-step base, and an alkylating-step
solvent, further comprises isolating the precipitate of the compound of
Formula (IIk) from the filtered mixture.

[0425] In some embodiments, isolating the precipitate of the compound of
Formula (IIk) is conducted by filtration.

VII. Hydrolyzing Step

[0426] One aspect of the present invention pertains to processes for
preparing (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-t-
etrahydrocyclopenta[b]indol-3-yl)acetic acid of Formula (Ia):

##STR00071##

comprising the step of hydrolyzing a compound of Formula (IIk):

##STR00072##

[0427] R3 is C1-C6 alkyl;

in the presence of a lipase and a hydrolyzing-step solvent to form
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia).

[0428] In some embodiments, R3 is methyl or ethyl.

[0429] In some embodiments, R3 is ethyl.

[0430] In some embodiments, the lipase is selected from the group
consisting of lipase B Candida Antarctica, lipase Mucor miehei, and P.
fluorescens.

[0431] In some embodiments, the lipase is Candida antarctica lipase B.

[0432] In some embodiments, the lipase is immobilized Candida antarctica
lipase B.

[0433] In some embodiments, the hydrolyzing-step solvent comprises a
suitable solvent.

[0440] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted in the presence of a phosphate buffer.

[0441] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted in the presence of a phosphate buffer at a pH of about 6.0
to about 9.0.

[0442] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted in the presence of a phosphate buffer at a pH of about 7.0
to about 8.5.

[0443] In some embodiments, the step of hydrolyzing the compound of
Formula (Ilk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted in the presence of a phosphate buffer at a pH of about 7.3
to about 8.3.

[0444] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted in the presence of a phosphate buffer at a pH of about 7.6
to about 8.0.

[0445] In some embodiments, the step of hydrolyzing the compound of
Formula (Ilk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted in the presence of a phosphate buffer at a pH of about 7.8.

[0446] In some embodiments, the phosphate buffer is a sodium phosphate
buffer.

[0447] In some embodiments, the phosphate buffer is a potassium phosphate
buffer.

[0448] In some embodiments, the step of hydrolyzing the compound of
Formula (Ilk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted at a temperature of about 0° C. to about 75°
C.

[0449] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted at a temperature of about 20° C. to about 65°
C.

[0450] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted at a temperature of about 30° C. to about 55°
C.

[0451] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted at a temperature of about 35° C. to about 45°
C.

[0452] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted at a temperature of about 40° C.

[0453] In some embodiments, the step of hydrolyzing the compound of
Formula (IIIk) in the presence of a lipase and a hydrolyzing-step
solvent, further comprises the step of isolating the
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia).

[0454] In some embodiments, after the step of isolating
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia),
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) has an enantiomeric
excess of about 95% or greater.

[0455] In some embodiments, after the step of isolating
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia),
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) has an enantiomeric
excess of about 98% or greater.

[0456] In some embodiments, after the step of isolating
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia),
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) has an enantiomeric
excess of about 99% or greater.

VIII. Hydrolyzing Step and Salt Formation Step

[0457] One aspect of the present invention pertains to processes for
preparing an L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia):

##STR00074##

[0458] comprising the following steps:

a) hydrolyzing a compound of Formula (IIk):

##STR00075##

[0459] wherein R3 is C1-C6 alkyl;

in the presence of a lipase and a hydrolyzing-step solvent to form
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia); and b) contacting
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid (Formula (Ia)) with L-arginine or a
salt thereof, in the presence of a contacting-step solvent and H2O
to form the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia).

[0460] VIIIa. Hydrolyzing Step a)

[0461] In some embodiments, R3 is methyl or ethyl.

[0462] In some embodiments, R3 is ethyl.

[0463] In some embodiments, the lipase is Candida antarctica lipase B.

[0464] In some embodiments, the lipase is immobilized Candida antarctica
lipase B.

[0465] In some embodiments, the hydrolyzing-step solvent comprises a
suitable solvent.

[0467] In some embodiments, the hydrolyzing-step solvent comprises
acetonitrile.

[0468] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent,
is conducted wherein: [0469] the compound of Formula (IIIk) is:

[0472] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted in the presence of a phosphate buffer.

[0473] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted in the presence of a phosphate buffer at a pH of about 6.0
to about 9.0.

[0474] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted in the presence of a phosphate buffer at a pH of about 7.0
to about 8.5.

[0475] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted in the presence of a phosphate buffer at a pH of about 7.3
to about 8.3.

[0476] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted in the presence of a phosphate buffer at a pH of about 7.6
to about 8.0.

[0477] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted in the presence of a phosphate buffer at a pH of about 7.8.

[0478] In some embodiments, the phosphate buffer is a sodium phosphate
buffer.

[0479] In some embodiments, the phosphate buffer is a potassium phosphate
buffer.

[0480] In some embodiments, the step of hydrolyzing the compound of
Formula (Ilk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted at a temperature of about 0° C. to about 75°
C.

[0481] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted at a temperature of about 20° C. to about 65°
C.

[0482] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted at a temperature of about 30° C. to about 55°
C.

[0483] In some embodiments, the step of hydrolyzing the compound of
Formula (IIk) in the presence of a lipase and a hydrolyzing-step solvent
is conducted at a temperature of about 35° C. to about 45°
C.

[0484] In some embodiments, the step of hydrolyzing the compound of
Formula (Ilk) in the presence of a lipase and a hydrolyzing-step solvent,
further comprises the step of isolating
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia).

[0485] In some embodiments, after the step of isolating
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia),
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) has an enantiomeric
excess of about 95% or greater.

[0486] In some embodiments, after the step of isolating
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia),
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) has an enantiomeric
excess of about 98% or greater.

[0487] In some embodiments, after the step of isolating
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia),
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) has an enantiomeric
excess of about 99% or greater.

Representative HPLC Method for Chemical Purity Determination

[0488] It is understood that the HPLC methods that retention times
provided herein are approximate and are depend on numerous parameters
that are know by those skilled in art, for example, the column, the
column temperature, flow rate, solvent(s), the HPLC system; and the like.
A standard for any of the compounds described herein can be readily
prepared and the retention time easily determined for a HPLC system and
conditions other than those described herein.

[0489] A representative HPLC method to determine the chemical purity of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[13]indol-3-yl)acetic acid of Formula (Ia) or the L-arginine salt
thereof is described below:

[0501] A representative HPLC method to determine the enantiomeric excess
of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahyd-
rocyclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is described below:

[0513] The retention time for
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid using the above conditions is about
24.9 minutes.

[0514] The retention time for
(5)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid using the above conditions is about
30.3 minutes.

[0515] VIIIb. Contacting Step b)--Salt Formation Step

[0516] In some embodiments, the contacting-step solvent comprises a
suitable solvent.

[0517] In some embodiments, the contacting-step solvent comprises a
C1-C6 alcohol.

[0518] In some embodiments, the contacting-step solvent comprises
isopropyl alcohol.

[0519] In some embodiments, the contacting in step b), is conducted under
a substantially inert atmosphere.

[0520] In some embodiments, the contacting in step b), is conducted under
a substantially inert atmosphere comprising argon or nitrogen.

[0521] In some embodiments, the contacting in step b), is conducted under
a substantially inert atmosphere comprising nitrogen.

[0522] In some embodiments, the molar ratio between
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[1)]indol-3-yl)acetic acid (Formula (Ia)) and L-arginine is about
1.0:1.0 to about 1.0:1.2.

[0523] In some embodiments, the molar ratio between
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid (Formula (Ia)) and L-arginine is about
1.0:1.0.

[0524] In some embodiments, the contacting in step b) further comprises
the step of adding an aqueous solution of L-arginine to a first
contacting mixture comprising
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[1)]indol-3-yl)acetic acid (Formula (Ia)) and the C1-C6
alcohol to form a second contacting mixture.

[0525] In some embodiments, the first contacting mixture is at a
temperature of about 45° C. to about 75° C.

[0526] In some embodiments, the first contacting mixture is at a
temperature of about 50° C. to about 70° C.

[0527] In some embodiments, the first contacting mixture is at a
temperature of about 55° C. to about 65° C.

[0528] In some embodiments, the first contacting mixture is at a
temperature of about 60° C.

[0529] In some embodiments, further comprising the steps of cooling the
second contacting mixture and crystallizing the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia).

[0530] In some embodiments, the cooling is conducted at a rate of about
0.04° C./minute to about 4.0° C./minute.

[0531] In some embodiments, the cooling is conducted at a rate of about
0.1° C./minute to about 2.0° C./minute.

[0532] In some embodiments, the cooling is conducted at a rate of about
0.4° C./minute to about 1.0° C./minute.

[0533] In some embodiments, the cooling is conducted at a rate of about
0.4° C./minute.

[0534] In some embodiments, contacting
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid (Formula (Ia)) with L-arginine or a
salt thereof, in the presence of a contacting-step solvent and H2O,
further comprises the step of isolating the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia).

[0535] In some embodiments, the isolating is conducted by filtration.

[0536] In some embodiments, after isolating, the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) has a purity of about
95% or greater as determined by HPLC.

[0537] In some embodiments, after isolating, the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) has a purity of about
98% or greater as determined by HPLC.

[0538] In some embodiments, after isolating, the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) has a purity of about
99% or greater as determined by HPLC.

[0539] In some embodiments, after isolating the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia), the
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) has an enantiomeric
excess of about 95% or greater.

[0540] In some embodiments, after isolating the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia), the
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) has an enantiomeric
excess of about 98% or greater.

[0541] In some embodiments, after isolating the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia), the
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) has an enantiomeric
excess of about 99% or greater.

[0542] A representative HPLC method to determine the enantiomeric excess
of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahyd-
rocyclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is as described
above.

[0543] A representative HPLC method for the analysis of L-arginine for the
L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is described below.

[0556] The retention time of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid present in the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid using the above conditions is about 1.2
minutes.

[0557] The retention time of L-arginine present in the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[13]indol-3-yl)acetic acid using the above conditions is about
8.6 minutes.

[0558] The processes described herein can be monitored according to any
suitable method known in the art. For example, product formation can be
monitored by spectroscopic means, such as nuclear magnetic resonance
spectroscopy (e.g., 1H or 13C), infrared spectroscopy,
spectrophotometry (e.g., UV-visible), or mass spectrometry, or by
chromatography such as high performance liquid chromatography (HPLC) or
thin layer chromatography.

[0559] In some embodiments, preparation of compounds can involve the
protection and deprotection of various chemical groups. The need for
protection and deprotection, and the selection of appropriate protecting
groups can be readily determined by one skilled in the art. The chemistry
of protecting groups can be found, for example, in Greene and Wuts,
Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, 1999.

[0560] The reactions of the processes described herein can be carried out
in suitable solvents which can be readily selected by one of skill in the
art of organic synthesis. Suitable solvents can be substantially
nonreactive with the starting materials (reactants), the intermediates,
or products at the temperatures at which the reactions are carried out,
e.g., temperatures which can range from the solvent's freezing
temperature to the solvent's boiling temperature. A given reaction can be
carried out in one solvent or a mixture of more than one solvent.
Depending on the particular reaction step, suitable solvents for a
particular reaction step can be selected. In some embodiments, reactions
can be carried out in the absence of solvent, such as when at least one
of the reagents is a liquid or gas.

wherein R, R', and R'' may be the same or different. In some embodiments,
R, R', and R'' are each independently selected from H and C1-C6
alkyl. In some embodiments, R, R', and R'' are each independently
selected from H and C1-C4 alkyl. In some embodiments, R, R',
and R'' are each independently selected from H and C1-C2 alkyl.

[0565] Supercritical carbon dioxide can also be used as a solvent.

[0566] The reactions of the processes described herein can be carried out
at appropriate temperatures which can be readily determined by one
skilled in the art. Reaction temperatures will depend on, for example,
the melting and boiling points of the reagents and solvent, if present;
the thermodynamics of the reaction (e.g., vigorously exothermic reactions
may need to be carried out at reduced temperatures); and the kinetics of
the reaction (e.g., a high activation energy barrier may need elevated
temperatures).

[0567] The reactions of the processes described herein can be carried out
in air or under an inert atmosphere. Typically, reactions containing
reagents or products that are substantially reactive with air can be
carried out using air-sensitive synthetic techniques that are well known
to one skilled in the art.

[0568] In some embodiments, preparation of compounds can involve the
addition of acids or bases to effect, for example, catalysis of a desired
reaction or formation of salt forms such as acid addition salts.

[0571] The compounds described herein can be asymmetric (e.g., having one
or more stereocenters). All stereoisomers, such as enantiomers and
diastereomers, are intended unless otherwise indicated. Salts of the
present invention that contain asymmetrically substituted carbon atoms
can be isolated in optically active or racemic forms. Methods on how to
prepare optically active forms from optically active starting materials
are known in the art, such as by resolution of racemic mixtures or by
stereoselective synthesis.

[0572] The processes described herein can be stereoselective such that any
given reaction starting with one or more chiral reagents enriched in one
stereoisomer forms a product that is also enriched in one stereoisomer.
The reaction can be conducted such that the product of the reaction
substantially retains one or more chiral centers present in the starting
materials. The reaction can also be conducted such that the product of
the reaction contains a chiral center that is substantially inverted
relative to a corresponding chiral center present in the starting
materials.

[0573] Resolution of racemic mixtures of compounds can be carried out by
any of numerous methods known in the art. An example method includes
fractional recrystallization (for example, diastereomeric salt
resolution) using a "chiral resolving acid" which is an optically active,
salt-forming organic acid. Suitable resolving agents for fractional
recrystallization methods are, for example, optically active acids, such
as the D and L forms of tartaric acid, diacetyltartaric acid,
dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the
various optically active camphorsulfonic acids such as
β-camphorsulfonic acid. Other resolving agents suitable for
fractional crystallization methods include stereoisomerically pure forms
of β-methylbenzylamine (e.g., S and R forms, or diastereomerically
pure forms), 2-phenylglycinol, norephedrine, ephedrine,
N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the
like.

[0574] Resolution of racemic mixtures can also be carried out by elution
on a column packed with an optically active resolving agent (e.g.,
dinitrobenzoylphenylglycine). Suitable elution solvent composition can be
determined by one skilled in the art.

[0575] The compounds described herein and salts thereof can also include
all isotopes of atoms occurring in the intermediates or final compounds
or salts thereof. Isotopes include those atoms having the same atomic
number but different mass numbers. For example, isotopes of hydrogen
include tritium and deuterium.

[0576] The compounds described herein and salts thereof can also include
tautomeric forms, such as keto-enol tautomers. Tautomeric forms can be in
equilibrium or sterically locked into one form by appropriate
substitution.

[0577] Upon carrying out preparation of compounds according to the
processes described herein, the usual isolation and purification
operations such as concentration, filtration, extraction, solid-phase
extraction, recrystallization, chromatography, and the like may be used,
to isolate the desired products.

Uses and Intermediates

[0578] One aspect of the present invention provides, inter alia,
intermediates prepared by any of the processes described herein.

[0579] The present invention further provides pharmaceutical compositions
comprising compounds prepared by any of the processes as described
herein.

[0580] The present invention further provides processes of preparing a
pharmaceutical composition comprising admixing Compound of Formula (Ia)
or a salt thereof with a pharmaceutically acceptable carrier, wherein the
Compound of Formula (Ia) or a salt thereof is prepared by any of the
processes as described herein.

[0581] The present invention further provides intermediates, as described
herein, for use in processes for preparing pharmaceutical compositions
for treating an S1P1 receptor-associated disorder in an individual.

[0582] The present invention further provides uses of compounds, as
described herein, in processes for preparing pharmaceutical compositions
for treating an S1P1 receptor-associated disorder.

[0583] One aspect of the present invention pertains to compounds
represented by any of the formulae described herein.

[0584] One aspect of the present invention pertains to compounds
represented by any of the formulae described herein for use in a process
for preparing a pharmaceutical composition for treating an S1P1
receptor-associated disorder in an individual.

[0585] One aspect of the present invention pertains to compounds
represented by any of the formulae described herein prepared according to
any of the processes described herein.

[0586] One aspect of the present invention pertains to compounds
represented by any of the formulae described herein prepared according to
any of the processes described herein, for use in a process for preparing
a pharmaceutical composition for treating an S1P1 receptor-associated
disorder in an individual.

[0587] Compound of Formula (IIb)

[0588] One aspect of the present invention pertains to a compound that is
1-cyclopentyl-2-(trifluoromethyl)benzene of Formula (IIb):

##STR00078##

[0589] One aspect of the present invention pertains to a compound that is
1-cyclopentyl-2-(trifluoromethyl)benzene of Formula (IIb):

##STR00079##

for use in a process for preparing a pharmaceutical composition for
treating an S1P1 receptor-associated disorder in an individual.

[0590] One aspect of the present invention pertains to a compound that is
1-cyclopentyl-2-(trifluoromethyl)benzene of Formula (IIb) prepared
according to any of the processes described herein.

[0591] One aspect of the present invention pertains to a compound that is
1-cyclopentyl-2-(trifluoromethyl)benzene of Formula (IIb) prepared
according to any of the processes described herein, for use in a process
for preparing a pharmaceutical composition for treating an S1P1
receptor-associated disorder in an individual.

[0592] Compound of Formula (IIc)

[0593] One aspect of the present invention pertains to a compound that is
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene of Formula
(IIc):

##STR00080##

[0594] One aspect of the present invention pertains to a compound that is
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene of Formula
(IIc):

##STR00081##

for use in a process for preparing a pharmaceutical composition for
treating an S1P1 receptor-associated disorder in an individual.

[0595] One aspect of the present invention pertains to a compound that is
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene of Formula
(IIc) prepared according to any of the processes described herein.

[0596] One aspect of the present invention pertains to a compound that is
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene of Formula
(IIc) prepared according to any of the processes described herein, for
use in a process for preparing a pharmaceutical composition for treating
an S1P1 receptor-associated disorder in an individual.

[0597] Compounds of Formula (IIi)

[0598] One aspect of the present invention pertains to a compound of
Formula (IIi):

##STR00082##

[0599] wherein R3 is C1-C6 alkyl; and R4, R5, and
R6 are each selected independently from the group consisting of H,
C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4
haloalkyl, C1-C4 haloalkoxy, and nitro.

[0600] In some embodiments, R3 is ethyl.

[0601] In some embodiments, R4, R5, and R6 are each H.

[0602] In some embodiments, R3 is ethyl, and R4, R5, and
R6 are each H.

[0603] One aspect of the present invention pertains to uses of a compound
of Formula (IIi):

##STR00083##

[0604] wherein R3 is C1-C6 alkyl; and R4, R5, and
R6 are each selected independently from the group consisting of H,
C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4
haloalkyl, C1-C4 haloalkoxy, and nitro; in the manufacture of a
medicament for treating an S1P1 receptor-associated disorder.

[0605] One aspect of the present invention pertains to uses of a compound
of the formula:

##STR00084##

in the manufacture of a medicament for treating an S1P1
receptor-associated disorder.

[0606] One aspect of the present invention pertains to uses of a compound
of Formula (IIi):

##STR00085##

[0607] wherein R3 is C1-C6 alkyl; and R4, R5, and
R6 are each selected independently from the group consisting of H,
C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4
haloalkyl, C1-C4 haloalkoxy, and nitro; in a process for
preparing a pharmaceutical composition for treating an S1P1
receptor-associated disorder in an individual.

[0608] One aspect of the present invention pertains to a compound of
Formula (IIi):

##STR00086##

[0609] wherein R3 is C1-C6 alkyl; and R4, R5, and
R6 are each selected independently from the group consisting of H,
C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4
haloalkyl, C1-C4 haloalkoxy, and nitro; for use in a process
for preparing a pharmaceutical composition for treating an S1P1
receptor-associated disorder in an individual.

[0610] One aspect of the present invention pertains to a compound of
Formula (IIi) prepared according to any of the processes described
herein.

[0611] One aspect of the present invention pertains to a compound of
Formula (IIi) prepared according to any of the processes described
herein, for use in a process for preparing a pharmaceutical composition
for treating an S1P1 receptor-associated disorder in an individual.

[0612] Compounds of Formula (IIj)

[0613] One aspect of the present invention pertains to a compound of
Formula (IIj):

##STR00087##

[0614] wherein R3 is C1-C6 alkyl.

[0615] One aspect of the present invention pertains to a compound of
Formula (IIj):

##STR00088##

[0616] wherein R3 is C1-C6 alkyl; for use in a process for
preparing a pharmaceutical composition for treating an S1P1
receptor-associated disorder in an individual.

[0617] One aspect of the present invention pertains to a compound of
Formula (IIj) prepared according to any of the processes described
herein.

[0618] One aspect of the present invention pertains to a compound of
Formula (IIj) prepared according to any of the processes described
herein, for use in a process for preparing a pharmaceutical composition
for treating an S1P1 receptor-associated disorder in an individual.

[0619] In some embodiments, R3 is ethyl.

[0620] In some embodiments, R3 is other than ethyl.

[0621] In some embodiments, R3 is other than methyl.

[0622] Compounds of Formula (IIk)

[0623] One aspect of the present invention pertains to a compound of
Formula (IIk):

##STR00089##

[0624] wherein R3 is C1-C6 alkyl.

[0625] One aspect of the present invention pertains to a compound of
Formula (IIk):

##STR00090##

[0626] wherein R3 is C1-C6 alkyl; for use in a process for
preparing a pharmaceutical composition for treating an S1P1
receptor-associated disorder in an individual.

[0627] One aspect of the present invention pertains to a compound of
Formula (IIk) prepared according to any of the processes described
herein.

[0628] One aspect of the present invention pertains to a compound of
Formula (IIk) prepared according to any of the processes described
herein, for use in a process for preparing a pharmaceutical composition
for treating an S1P1 receptor-associated disorder in an individual.

[0629] In some embodiments, R3 is ethyl.

[0630] In some embodiments, R3 is other than ethyl.

[0631] In some embodiments, R3 is other than methyl.

[0632] Compounds of Formula (Ia)

[0633] One aspect of the present invention pertains to pharmaceutical
compositions comprising
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia), or a salt thereof:

##STR00091##

and a pharmaceutically acceptable carrier, wherein the
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is prepared according
to any of the processes described herein.

[0634] In some embodiments,
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is used for treating an
S1P1 receptor-associated disorder in an individual, wherein
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is prepared according
to any of the processes described herein.

[0635] In some embodiments, the pharmaceutical composition comprising
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is used for treating an
S1P1 receptor-associated disorder in an individual, wherein
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is prepared according
to any of the processes described herein.

[0636] One aspect of the present invention pertains to processes of
preparing a pharmaceutical composition comprising admixing
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia), or a salt thereof:

##STR00092##

and a pharmaceutically acceptable carrier, wherein the
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is prepared according
to any of the processes described herein.

[0637] One aspect of the present invention pertains to
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta indol-3-yl)acetic acid of Formula (Ia) or a salt thereof,
prepared according to any of the processes described herein.

[0638] One aspect of the present invention pertains to
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) or a salt thereof,
prepared according to any of the processes described herein, for use in a
process for preparing a pharmaceutical composition for treating an S1P1
receptor-associated disorder in an individual.

[0639] L-Arginine salt of Compound of Formula (Ia)

[0640] One aspect of the present invention pertains to pharmaceutical
compositions comprising an L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia):

##STR00093##

and a pharmaceutically acceptable carrier, wherein the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is prepared according
to any of the processes described herein.

[0641] In some embodiments, L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is used for treating an
S1P1 receptor-associated disorder in an individual, wherein the
L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is prepared according
to any of the processes described herein.

[0642] In some embodiments, the pharmaceutical composition comprising an
L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is used for treating an
S1P1 receptor-associated disorder in an individual, wherein the
L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is prepared according
to any of the processes described herein.

[0643] One aspect of the present invention pertains to processes of
preparing a pharmaceutical composition comprising admixing an L-arginine
salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tet-
rahydrocyclopenta[b]indol-3-yl)acetic acid of Formula (Ia):

##STR00094##

and a pharmaceutically acceptable carrier, wherein the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid of Formula (Ia) is prepared according
to any of the processes described herein.

[0644] One aspect of the present invention pertains to the L-arginine salt
of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahyd-
rocyclopenta[b]indol-3-yl)acetic acid of Formula (Ia) or a salt thereof,
prepared according to any of the processes described herein.

[0645] One aspect of the present invention pertains to the L-arginine salt
of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahyd-
rocyclopenta[b]indol-3-yl)acetic acid of Formula (Ia) or a salt thereof,
prepared according to any of the processes described herein, for use in a
process for preparing a pharmaceutical composition for treating an S1P1
receptor-associated disorder in an individual.

[0647] That agonism of endothelial S1P1 receptors has a broader role in
promoting vascular integrity is supported by work implicating the S1P1
receptor in capillary integrity in mouse skin and lung (Sanna et al., Nat
Chem. Biol., 2:434-441, 2006). Vascular integrity can be compromised by
inflammatory processes, for example as may derive from sepsis, major
trauma and surgery so as to lead to acute lung injury or respiratory
distress syndrome (Johan Groeneveld, Vascul. Pharmacol., 39:247-256,
2003).

[0652] Recently, FTY720 has been reported to have anti-viral activity.
Specific data has been presented in the lymphocytic choriomeningitis
virus (LCMV) mouse model, wherein the mice were infected with either the
Armstrong or the clone 13 strain of LCMV (Premenko-Lanier et al., Nature,
454, 894, 2008).

[0654] It has also been recently reported that a short-term high dose of
FTY720 rapidly reduced ocular infiltrates in experimental autoimmune
uveoretinitis. When given in the early stages of ocular inflammation,
FTY720 rapidly prevented retinal damage. It was reported to not only
prevent infiltration of target organs, but also reduce existing
infiltration (Raveney et al., Arch. Ophthalmol. 126(10), 1390, 2008).

[0655] It has been reported that treatment with FTY720 relieved
ovariectomy-induced osteoporosis in mice by reducing the number of mature
osteoclasts attached to the bone surface. The data provided evidence that
SIP controled the migratory behaviour of osteoclast precursors,
dynamically regulating bone mineral homeostasis (Ishii et al., Nature,
458(7237), 524-528, 2009).

[0657] Agonism of the S1P1 receptor has also been reported to mediate
migration of neural stem cells toward injured areas of the central
nervous system (CNS), including in a rat model of spinal cord injury
(Kimura et al., Stem Cells, 25:115-124, 2007).

[0658] Agonism of the S1P1 receptor has been implicated in the inhibition
of keratinocyte proliferation (Sauer et al., J. Biol. Chem.,
279:38471-38479, 2004), consistent with reports that SIP inhibits
keratinocyte proliferation (Kim et al., Cell Signal, 16:89-95, 2004). The
hyperproliferation of keratinocytes at the entrance to the hair follicle,
which can then become blocked, and an associated inflammation are
significant pathogenetic factors of acne (Koreck et al., Dermatology,
206:96-105, 2003; Webster, Cutis, 76:4-7, 2005).

[0659] FTY720 has been reported to have therapeutic efficacy in inhibiting
pathologic angiogenesis, such as that as may occur in tumor development.
Inhibition of angiogenesis by FTY720 is thought to involve agonism of the
S1P1 receptor (Oo et al., J. Biol. Chem., 282; 9082-9089, 2007; Schmid et
al., J. Cell Biochem., 101:259-270, 2007). FTY720 has been reported to
have therapeutic efficacy for inhibiting primary and metastatic tumor
growth in a mouse model of melanoma (LaMontagne et al., Cancer Res.,
66:221-231, 2006). FTY720 has been reported to have therapeutic efficacy
in a mouse model for metastatic hepatocellular carcinoma (Lee et al.,
Clin. Cancer Res., 11:84588466, 2005).

[0661] Cyclosporin A and FK506 (calcineurin inhibitors) are drugs used to
prevent rejection of transplanted organs. Although they are effective in
delaying or suppressing transplant rejection, classical
immunosuppressants such as cyclosporin A and FK506 are known to cause
several undesirable side effects including nephrotoxicity, neurotoxicity,
β-cell toxicity and gastrointestinal discomfort. There is an unmet
need in organ transplantation for an immunosuppressant without these side
effects which is effective as a monotherapy or in combination with a
classical immunosuppressant for inhibiting migration of, e.g.,
alloantigen-reactive T-cells to the grafted tissue, thereby prolonging
graft survival.

[0662] FTY720 has been shown to have therapeutic efficacy in transplant
rejection both as a monotherapy and in synergistic combination with a
classical immunosuppressant, including cyclosporin A, FK506 and RAD (an
mTOR inhibitor). It has been shown that, unlike the classical
immunosuppressants cyclosporin A, FK506 and RAD, FTY720 has efficacy for
prolonging graft survival without inducing general immunosuppression, and
this difference in drug action is believed to be relevant to the
synergism observed for the combination (Brinkmann et al., Transplant
Proc., 33:530-531, 2001; Brinkmann et al., Transplantation, 72:764-769,
2001).

[0663] Agonism of the S1P1 receptor has been reported to have therapeutic
efficacy for prolonging allograft survival in mouse and rat skin
allograft models (Lima et al., Transplant Proc., 36:1015-1017, 2004; Yan
et al., Bioorg. & Med. Chem. Lett., 16:3679-3683, 2006). FTY720 has been
reported to have therapeutic efficacy for prolonging allograft survival
in a rat cardiac allograft model (Suzuki et al., Transpl. Immunol.,
4:252-255, 1996). FTY720 has been reported to act synergistically with
cyclosporin A to prolong rat skin allograft survival (Yanagawa et al., J.
Immunol., 160:5493-5499, 1998), to act synergistically with cyclosporin A
and with FK506 to prolong rat cardiac allograft survival, and to act
synergistically with cyclosporin A to prolong canine renal allograft
survival and monkey renal allograft survival (Chiba et al., Cell Mol.
Biol., 3:11-19, 2006). KRP-203, an SIP receptor agonist has been reported
to have therapeutic efficacy for prolonging allograft survival in a rat
skin allograft model and both as monotherapy and in synergistic
combination with cyclosporin A in a rat cardiac allograft model (Shimizu
et al., Circulation, 111:222-229, 2005). KRP-203 also has been reported
to have therapeutic efficacy in combination with mycophenolate mofetil
(MMF; a prodrug for which the active metabolite is mycophenolic acid, an
inhibitor of purine biosynthesis) for prolonging allograft survival both
in a rat renal allograft model and in a rat cardiac allograft model
(Suzuki et al., J. Heart Lung Transplant, 25:302-209, 2006; Fujishiro et
al., J. Heart Lung Transplant, 25:825-833, 2006). It has been reported
that an agonist of the S1P1 receptor, AUY954, in combination with a
subtherapeutic dose of RAD001 (Certican/Everolimus, an mTOR inhibitor)
can prolong rat cardiac allograft survival (Pan et al., Chemistry &
Biology, 13:1227-1234, 2006). In a rat small bowel allograft model,
FTY720 has been reported to act synergistically with cyclosporin A to
prolong small bowel allograft survival (Sakagawa et al., Transpl.
Immunol., 13:161-168, 2004). FTY720 has been reported to have therapeutic
efficacy in a mouse islet graft model (Fu et al., Transplantation,
73:1425-1430, 2002; Liu et al., Microsurgery, 27:300-304; 2007) and in a
study using human islet cells to evidence no detrimental effects on human
islet function (Truong et al., American Journal of Transplantation,
7:2031-2038, 2007).

[0664] FTY720 has been reported to reduce the nociceptive behavior in the
spared nerve injury model for neuropathic pain which does not depend on
prostaglandin synthesis (O. Costu et al., Journal of Cellular and
Molecular Medicine 12(3), 995-1004, 2008).

[0667] In one embodiment, the present invention encompasses compounds
which are agonists of the S1P1 receptor having selectivity over the S1P3
receptor. The S1P3 receptor, and not the S1P1 receptor, has been directly
implicated in bradycardia (Sanna et al., J. Biol. Chem., 279:13839-13848,
2004). An S1P1 receptor agonist selective over at least the S1P3 receptor
has advantages over current therapies by virtue of an enhanced
therapeutic window, allowing better tolerability with higher dosing and
thus improving efficacy as therapy. The present invention encompasses
compounds which are agonists of the S1P1 receptor and which exhibit no or
substantially no activity for bradycardia.

[0668] S1P1 receptor agonists are useful for treating or preventing
conditions where suppression of the immune system or agonism of the S1P1
receptor is in order, such as diseases and disorders mediated by
lymphocytes, transplant rejection, autoimmune diseases and disorders,
inflammatory diseases and disorders, and conditions that have an
underlying defect in vascular integrity or that relate to angiogenesis
such as may be pathologic.

[0669] S1P1 receptor agonists are useful for treating or preventing
conditions where suppression of the immune system or agonism of the S1P1
receptor is in order, such as diseases and disorders mediated by
lymphocytes, transplant rejection, autoimmune diseases and disorders,
inflammatory diseases and disorders (e.g., acute and chronic inflammatory
conditions), cancer, and conditions that have an underlying defect in
vascular integrity or that are associated with angiogenesis such as may
be pathologic (e.g., as may occur in inflammation, tumor development and
atherosclerosis). Such conditions where suppression of the immune system
or agonism of the S1P1 receptor is in order include diseases and
disorders mediated by lymphocytes; conditions that have an underlying
defect in vascular integrity; autoimmune diseases and disorders;
inflammatory diseases and disorders (e.g., acute and chronic inflammatory
conditions); acute or chronic rejection of cells; tissue or solid organ
grafts; arthritis, including psoriatic arthritis, and rheumatoid
arthritis; diabetes, including type I diabetes; demyelinating disease,
including multiple sclerosis; ischemia-reperfusion injury, including
renal and cardiac ischemia-reperfusion injury; inflammatory skin disease,
including psoriasis, atopic dermatitis, and acne; hyperproliferative skin
disease, including acne; inflammatory bowel disease, including Crohn's
disease, and ulcerative colitis; systemic lupus erythematosis; asthma;
uveitis; myocarditis; allergy; atherosclerosis; brain inflammation,
including Alzheimer's disease, and brain inflammatory reaction following
traumatic brain injury; central nervous system disease, including spinal
cord injury, or cerebral infarction; pathologic angiogenesis, including
as may occur in primary and metastatic tumor growth; rheumatoid
arthritis; diabetic retinopathy, atherosclerosis; cancer; chronic
pulmonary disease; acute lung injury; acute respiratory disease syndrome;
sepsis; and the like. In addition, S1P1 receptor agonists are useful for
treating microbial infections, and viral infections or diseases.

[0670] In some embodiments, the S1P1 receptor-associated disorder is a
disease or disorder mediated by lymphocytes.

[0671] In some embodiments, the S1P1 receptor-associated disorder is an
autoimmune disease or disorder.

[0672] In some embodiments, the S1P1 receptor-associated disorder is an
inflammatory disease or disorder.

[0673] In some embodiments, the S1P1 receptor-associated disorder is a
microbial infection or microbial disease.

[0674] In some embodiments, the S1P1 receptor-associated disorder is a
viral infection or viral disease.

[0675] In some embodiments, the S1P1 receptor-associated disorder is
cancer.

[0677] In some embodiments, the S1P1 receptor-associated disorder is
psoriasis.

[0678] In some embodiments, the S1P1 receptor-associated disorder is
rheumatoid arthritis.

[0679] In some embodiments, the S1P1 receptor-associated disorder is
Crohn's disease.

[0680] In some embodiments, the S1P1 receptor-associated disorder is
transplant rejection.

[0681] In some embodiments, the S1P1 receptor-associated disorder is
multiple sclerosis.

[0682] In some embodiments, the S1P1 receptor-associated disorder is
systemic lupus erythematosus.

[0683] In some embodiments, the S1P1 receptor-associated disorder is
ulcerative colitis.

[0684] In some embodiments, the S1P1 receptor-associated disorder is type
I diabetes.

[0685] In some embodiments, the S1P1 receptor-associated disorder is acne.

[0686] In some embodiments, the S1P1 receptor-associated disorder is
myocardial ischemia-reperfusion injury.

[0687] In some embodiments, the S1P1 receptor-associated disorder is
hypertensive nephropathy.

[0688] In some embodiments, the S1P1 receptor-associated disorder is
glomerulosclerosis.

[0689] In some embodiments, the S1P1 receptor-associated disorder is
gastritis.

[0690] In some embodiments, the S1P1 receptor-associated disorder is
polymyositis.

[0691] In some embodiments, the S1P1 receptor-associated disorder is
thyroiditis.

[0692] In some embodiments, the S1P1 receptor-associated disorder is
vitiligo.

[0693] In some embodiments, the S1P1 receptor-associated disorder is
hepatitis.

[0694] In some embodiments, the S1P1 receptor-associated disorder is
biliary cirrhosis.

Pharmaceutical Compositions

[0695] One aspect of the present invention pertains to compounds
represented by any of the formulae described herein used in the
preparation of pharmaceutical compositions.

[0696] A further aspect of the present invention pertains to
pharmaceutical compositions comprising Compound of Formula (Ia) or a
pharmaceutically acceptable salt thereof and one or more pharmaceutically
acceptable carriers. Some embodiments pertain to pharmaceutical
compositions comprising Compound of Formula (Ia) or a pharmaceutically
acceptable salt and a pharmaceutically acceptable carrier.

[0697] Some embodiments of the present invention include a method of
producing a pharmaceutical composition comprising admixing Compound of
Formula (Ia) or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.

[0698] Formulations may be prepared by any suitable method, typically by
uniformly mixing Compound of Formula (Ia) or a pharmaceutically
acceptable salt thereof with liquids or finely divided solid carriers, or
both, in the required proportions and then, if necessary, forming the
resulting mixture into a desired shape.

[0699] Conventional excipients, such as binding agents, fillers,
acceptable wetting agents, tabletting lubricants and disintegrants may be
used in tablets and capsules for oral administration. Liquid preparations
for oral administration may be in the form of solutions, emulsions,
aqueous or oily suspensions and syrups. Alternatively, the oral
preparations may be in the form of a dry powder that can be reconstituted
with water or another suitable liquid vehicle before use. Additional
additives such as suspending or emulsifying agents, non-aqueous vehicles
(including edible oils), preservatives and flavorings and colorants may
be added to the liquid preparations. Parenteral dosage forms may be
prepared by dissolving Compound of Formula (Ia) or a pharmaceutically
acceptable salt thereof in a suitable liquid vehicle and filter
sterilizing the solution before filling and sealing an appropriate vial
or ampule. These are just a few examples of the many appropriate methods
well known in the art for preparing dosage forms.

[0700] Compound of Formula (Ia) or a pharmaceutically acceptable salt
thereof can be formulated into pharmaceutical compositions using
techniques well known to those in the art. Suitable
pharmaceutically-acceptable carriers, outside those mentioned herein, are
known in the art; for example, see Remington, The Science and Practice of
Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins,
(Editors: Gennaro et al.)

[0701] While it is possible that, for use in treatment, Compound of
Formula (Ia) or a pharmaceutically acceptable salt thereof may, in an
alternative use, be administered as a raw or pure chemical, it is
preferable however to present the active ingredient as a pharmaceutical
formulation or composition further comprising a pharmaceutically
acceptable carrier.

[0702] The invention thus further relates to pharmaceutical formulations
comprising Compound of Formula (Ia) or a pharmaceutically acceptable salt
thereof, together with one or more pharmaceutically acceptable carriers
thereof and/or prophylactic ingredients. The carrier(s) must be
"acceptable" in the sense of being compatible with the other ingredients
of the formulation and not overly deleterious to the recipient thereof.
Typical procedures for making and identifying suitable hydrates and
solvates, outside those mentioned herein, are well known to those in the
art; see for example, pages 202-209 of K. J. Guillory, "Generation of
Polymorphs, Hydrates, Solvates, and Amorphous Solids," in: Polymorphism
in Pharmaceutical Solids, ed. Harry G. Brittain, Vol. 95, Marcel Dekker,
Inc., New York, 1999.

[0703] Pharmaceutical formulations include those suitable for oral,
rectal, nasal, topical (including buccal and sub-lingual), vaginal or
parenteral (including intramuscular, sub-cutaneous and intravenous)
administration or in a form suitable for administration by inhalation,
insufflation or by a transdermal patch. Transdermal patches dispense a
drug at a controlled rate by presenting the drug for absorption in an
efficient manner with a minimum of degradation of the drug. Typically,
transdermal patches comprise an impermeable backing layer, a single
pressure sensitive adhesive and a removable protective layer with a
release liner. One of ordinary skill in the art will understand and
appreciate the techniques appropriate for manufacturing a desired
efficacious transdermal patch based upon the needs of the artisan.

[0704] Compound of Formula (Ia) or a pharmaceutically acceptable salt
thereof, together with a conventional adjuvant, carrier, or diluent, may
thus be placed into the form of pharmaceutical formulations and unit
dosages thereof and in such form may be employed as solids, such as
tablets or filled capsules, or liquids such as solutions, suspensions,
emulsions, elixirs, gels or capsules filled with the same, all for oral
use, in the form of suppositories for rectal administration; or in the
form of sterile injectable solutions for parenteral (including
subcutaneous) use. Such pharmaceutical compositions and unit dosage forms
thereof may comprise conventional ingredients in conventional
proportions, with or without additional active ingredients and such unit
dosage forms may contain any suitable effective amount of the active
ingredient commensurate with the intended daily dosage range to be
employed.

[0705] For oral administration, the pharmaceutical composition may be in
the form of, for example, a tablet, capsule, suspension or liquid. The
pharmaceutical composition is preferably made in the form of a dosage
unit containing a particular amount of the active ingredient. Examples of
such dosage units are capsules, tablets, powders, granules or
suspensions, with conventional additives such as lactose, mannitol, corn
starch or potato starch; with binders such as crystalline cellulose,
cellulose derivatives, acacia, corn starch or gelatins; with
disintegrators such as corn starch, potato starch or sodium
carboxymethyl-cellulose; and with lubricants such as talc or magnesium
stearate. The active ingredient may also be administered by injection as
a composition wherein, for example, saline, dextrose or water may be used
as a suitable pharmaceutically acceptable carrier.

[0706] Compound of Formula (Ia) and pharmaceutically acceptable salts
thereof can be used as active ingredients in pharmaceutical compositions,
specifically as S1P1 receptor modulators. The term "active ingredient" in
the context of a "pharmaceutical composition" is intended to mean a
component of a pharmaceutical composition that provides the primary
pharmacological effect, as opposed to an "inactive ingredient" which
would generally be recognized as providing no pharmaceutical benefit.

[0707] The dose when using Compound of Formula (Ia) or a pharmaceutically
acceptable salt thereof can vary within wide limits and as is customary
and as is known to the physician, it is to be tailored to the individual
conditions in each individual case. It depends, for example, on the
nature and severity of the illness to be treated; on the condition of the
patient; on the formulation employed; on whether an acute or chronic
disease state is treated, or prophylaxis is conducted; or on whether
further active ingredients are administered in addition to Compound of
Formula (Ia) or a pharmaceutically acceptable salt thereof.
Representative doses of the present invention include, but are not
limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500
mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg
to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg
and about 0.001 mg to about 25 mg. Multiple doses may be administered
during the day, especially when relatively large amounts are deemed to be
needed, for example two, three or four doses. Depending on the individual
and as deemed appropriate from the patient's physician or caregiver it
may be necessary to deviate upward or downward from the doses described
herein.

[0708] The amount of active ingredient required for use in treatment will
vary not only with the particular ingredient selected but also with the
route of administration, the nature of the condition being treated and
the age and condition of the patient and will ultimately be at the
discretion of the attendant physician or clinician. In general, one
skilled in the art understands how to extrapolate in vivo data obtained
in a model system, typically an animal model, to another, such as a
human. In some circumstances, these extrapolations may merely be based on
the weight of the animal model in comparison to another, such as a
mammal, preferably a human, however, more often, these extrapolations are
not simply based on weights, but rather incorporate a variety of factors.
Representative factors include the type, age, weight, sex, diet and
medical condition of the patient, the severity of the disease, the route
of administration, pharmacological considerations such as the activity,
efficacy, pharmacokinetic and toxicology profiles of the particular
active ingredient employed, whether a drug delivery system is utilized,
on whether an acute or chronic disease state is being treated or
prophylaxis is conducted or on whether further active ingredients are
administered in addition to Compound of Formula (Ia) or a
pharmaceutically acceptable salt thereof as part of a drug combination.
The dosage regimen for treating a disease condition with Compound of
Formula (Ia) or a pharmaceutically acceptable salt thereof is selected in
accordance with a variety factors as cited above. Thus, the actual dosage
regimen employed may vary widely and therefore may deviate from a
preferred dosage regimen and one skilled in the art will recognize that
dosages and dosage regimens outside these typical ranges can be tested
and, where appropriate, may be used in the methods described herein.

[0709] The desired dose may conveniently be presented in a single dose or
as divided doses administered at appropriate intervals, for example, as
two, three, four or more sub-doses per day. The sub-dose itself may be
further divided, for example, into a number of discrete loosely spaced
administrations. The daily dose can be divided, especially when
relatively large amounts are administered as deemed appropriate, into
several, for example, two, three or four part administrations. If
appropriate, depending on individual behavior, it may be necessary to
deviate upward or downward from the daily dose indicated.

[0710] Compound of Formula (Ia) or a pharmaceutically acceptable salt
thereof can be administrated in a wide variety of oral and parenteral
dosage forms. It will be obvious to those skilled in the art that the
following dosage forms may comprise, as the active component, either
Compound of Formula (Ia) or a pharmaceutically acceptable salt thereof.

[0711] For preparing pharmaceutical compositions from Compound of Formula
(Ia) or a pharmaceutically acceptable salt thereof, the pharmaceutically
acceptable carrier can be either solid, liquid or a mixture of both.
Solid form preparations include powders, tablets, pills, capsules,
cachets, suppositories and dispersible granules. A solid carrier can be
one or more substances which may also act as diluents, flavoring agents,
solubilizers, lubricants, suspending agents, binders, preservatives,
tablet disintegrating agents, or an encapsulating material.

[0712] In powders, the carrier is a finely divided solid which is in a
mixture with the finely divided active component. In tablets, the active
component is mixed with the carrier having the necessary binding capacity
in suitable proportions and compacted to the desired shape and size. The
powders and tablets may contain varying percentages of the active
ingredient. A representative amount in a powder or tablet may contain
from 0.5 to about 90 percent of the active ingredient; however, an
artisan would know when amounts outside of this range are necessary.
Suitable carriers for powders and tablets are magnesium carbonate,
magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,
gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a
low melting wax, cocoa butter and the like. The term "preparation" is
intended to include the formulation of the active ingredient with
encapsulating material as a carrier providing a capsule in which the
active component, with or without carriers, is surrounded by a carrier,
and which is thus in association with it. Similarly, cachets and lozenges
are included. Tablets, powders, capsules, pills, cachets and lozenges can
be used as solid forms suitable for oral administration.

[0713] For preparing suppositories, a low melting wax, such as an
admixture of fatty acid glycerides or cocoa butter, is first melted and
the active component is dispersed homogeneously therein, as by stirring.
The molten homogenous mixture is then poured into convenient sized molds,
allowed to cool and thereby to solidify.

[0714] Formulations suitable for vaginal administration may be presented
as pessaries, tampons, creams, gels, pastes, foams or sprays containing,
in addition to the active ingredient, such carriers as are known in the
art to be appropriate.

[0715] Liquid form preparations include solutions, suspensions and
emulsions, for example, water or water-propylene glycol solutions. For
example, parenteral injection liquid preparations can be formulated as
solutions in aqueous polyethylene glycol solution. Injectable
preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable
dispersing or wetting agents and suspending agents. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a nontoxic parenterally acceptable diluent or solvent, for
example, as a solution in 1,3-butanediol. Among the acceptable vehicles
and solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid find use in the
preparation of injectables.

[0716] Compound of Formula (Ia) or a pharmaceutically acceptable salt
thereof may thus be formulated for parenteral administration (e.g. by
injection, for example bolus injection or continuous infusion) and may be
presented in unit dose form in ampoules, pre-filled syringes, small
volume infusion or in multi-dose containers with an added preservative.
The pharmaceutical compositions may take such forms as suspensions,
solutions, or emulsions in oily or aqueous vehicles and may contain
formulatory agents such as suspending, stabilizing and/or dispersing
agents. Alternatively, the active ingredient may be in powder form,
obtained by aseptic isolation of sterile solid or by lyophilization from
solution, for constitution with a suitable vehicle, e.g. sterile,
pyrogen-free water, before use.

[0717] Aqueous formulations suitable for oral use can be prepared by
dissolving or suspending the active component in water and adding
suitable colorants, flavors, stabilizing and thickening agents, as
desired.

[0718] Aqueous suspensions suitable for oral use can be made by dispersing
the finely divided active component in water with viscous material, such
as natural or synthetic gums, resins, methylcellulose, sodium
carboxymethylcellulose, or other well-known suspending agents.

[0719] Also included are solid form preparations which are intended to be
converted, shortly before use, to liquid form preparations for oral
administration. Such liquid forms include solutions, suspensions and
emulsions. These preparations may contain, in addition to the active
component, colorants, flavors, stabilizers, buffers, artificial and
natural sweeteners, dispersants, thickeners, solubilizing agents and the
like.

[0720] For topical administration to the epidermis Compound of Formula
(Ia) or a pharmaceutically acceptable salt thereof may be formulated as
ointments, creams or lotions, or as a transdermal patch.

[0721] Ointments and creams may, for example, be formulated with an
aqueous or oily base with the addition of suitable thickening and/or
gelling agents. Lotions may be formulated with an aqueous or oily base
and will in general also contain one or more emulsifying agents,
stabilizing agents, dispersing agents, suspending agents, thickening
agents, or coloring agents.

[0722] Formulations suitable for topical administration in the mouth
include lozenges comprising active agent in a flavored base, usually
sucrose and acacia or tragacanth; pastilles comprising the active
ingredient in an inert base such as gelatin and glycerin or sucrose and
acacia; and mouthwashes comprising the active ingredient in a suitable
liquid carrier.

[0723] Solutions or suspensions are applied directly to the nasal cavity
by conventional means, for example with a dropper, pipette or spray. The
formulations may be provided in single or multi-dose form. In the latter
case of a dropper or pipette, this may be achieved by the patient
administering an appropriate, predetermined volume of the solution or
suspension. In the case of a spray, this may be achieved for example by
means of a metering atomizing spray pump.

[0724] Administration to the respiratory tract may also be achieved by
means of an aerosol formulation in which the active ingredient is
provided in a pressurized pack with a suitable propellant. If Compound of
Formula (Ia) or a pharmaceutically acceptable salt thereof or
pharmaceutical compositions comprising them are administered as aerosols,
for example as nasal aerosols or by inhalation, this can be carried out,
for example, using a spray, a nebulizer, a pump nebulizer, an inhalation
apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical
forms for administration of Compound of Formula (Ia) or a
pharmaceutically acceptable salt thereof as an aerosol can be prepared by
processes well known to the person skilled in the art. For their
preparation, for example, solutions or dispersions of Compound of Formula
(Ia) or a pharmaceutically acceptable salt thereof in water,
water/alcohol mixtures or suitable saline solutions can be employed using
customary additives, for example benzyl alcohol or other suitable
preservatives, absorption enhancers for increasing the bioavailability,
solubilizers, dispersants and others and, if appropriate, customary
propellants, for example include carbon dioxide, CFCs, such as,
dichlorodifluoromethane, trichlorofluoromethane, or
dichlorotetrafluoroethane; and the like. The aerosol may conveniently
also contain a surfactant such as lecithin. The dose of drug may be
controlled by provision of a metered valve.

[0725] In formulations intended for administration to the respiratory
tract, including intranasal formulations, the pharmaceutical composition
will generally have a small particle size for example of the order of 10
microns or less. Such a particle size may be obtained by means known in
the art, for example by micronization. When desired, formulations adapted
to give sustained release of the active ingredient may be employed.

[0726] Alternatively the active ingredients may be provided in the form of
a dry powder, for example, a powder mix of the salt in a suitable powder
base such as lactose, starch, starch derivatives such as
hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
Conveniently the powder carrier will form a gel in the nasal cavity. The
powder composition may be presented in unit dose form for example in
capsules or cartridges of, e.g., gelatin, or blister packs from which the
powder may be administered by means of an inhaler.

[0727] The pharmaceutical preparations are preferably in unit dosage
forms. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as packeted tablets, capsules
and powders in vials or ampoules. Also, the unit dosage form can be a
capsule, tablet, cachet, or lozenge itself, or it can be the appropriate
number of any of these in packaged form.

[0728] Tablets or capsules for oral administration and liquids for
intravenous administration are preferred compositions.

[0730] The acid addition salts may be obtained as the direct products of
compound synthesis. In the alternative, the free base may be dissolved in
a suitable solvent containing the appropriate acid and the salt isolated
by evaporating the solvent or otherwise separating the salt and solvent.
Compound of Formula (Ia) or a pharmaceutically acceptable salt thereof
may form solvates with standard low molecular weight solvents using
methods known to the skilled artisan.

[0731] Compound of Formula (Ia) or a pharmaceutically acceptable salt
thereof can be converted to "pro-drugs." The term "pro-drugs" refers to
compounds that have been modified with specific chemical groups known in
the art and when administered into an individual these groups undergo
biotransformation to give the parent compound. Pro-drugs can thus be
viewed as compounds containing one or more specialized non-toxic
protective groups used in a transient manner to alter or to eliminate a
property of the compound. In one general aspect, the "pro-drug" approach
is utilized to facilitate oral absorption. A thorough discussion is
provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems
Vol. 14 of the A.C.S. Symposium Series; and in Bioreversible Carriers in
Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and
Pergamon Press, 1987.

[0732] Some embodiments of the present invention include a method of
producing a pharmaceutical composition for "combination-therapy"
comprising admixing Compound of Formula (Ia) or a pharmaceutically
acceptable salt thereof, together with at least one known pharmaceutical
agent as described herein and a pharmaceutically acceptable carrier.

[0733] It is noted that when S1P1 modulators are utilized as active
ingredients in pharmaceutical compositions, these are not intended for
use only in humans, but in other non-human mammals as well. Indeed,
recent advances in the area of animal health-care mandate that
consideration be given for the use of active agents, such as S1P1
modulators, for the treatment of an S1P1-associated disease or disorder
in companionship animals (e.g., cats, dogs, etc.) and in livestock
animals (e.g., cows, chickens, fish, etc.) Those of ordinary skill in the
art are readily credited with understanding the utility of such salts in
such settings.

Hydrates and Solvates

[0734] It is understood that when the phrase "pharmaceutically acceptable
salts, solvates and hydrates" is used in reference to a particular
compound herein, it is intended to embrace solvates and/or hydrates of
the particular compound, pharmaceutically acceptable salts of the
particular compound as well as solvates and/or hydrates of
pharmaceutically acceptable salts of the particular compound. It is also
understood by a person of ordinary skill in the art that hydrates are a
subgenus of solvates.

[0735] Compound of Formula (Ia) and pharmaceutically acceptable salts,
solvates and hydrates thereof can be administrated in a wide variety of
oral and parenteral dosage forms. It will be apparent to those skilled in
the art that the dosage forms may comprise, as the active component,
either Compound of Formula (Ia) and pharmaceutically acceptable salts,
solvates and hydrates thereof. Moreover, various hydrates and solvates of
Compound of Formula (Ia) and pharmaceutically acceptable salts thereof
will find use as intermediates in the manufacture of pharmaceutical
compositions. Typical procedures for making and identifying suitable
hydrates and solvates, outside those mentioned herein, are well known to
those in the art; see for example, pages 202-209 of K. J. Guillory,
"Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," in:
Polymorphism in Pharmaceutical Solids, ed. Harry G. Brittan, Vol. 95,
Marcel Dekker, Inc., New York, 1999. Accordingly, one aspect of the
present invention relates to processes for preparing hydrates and
solvates of Compound of Formula (Ia) and/or pharmaceutically acceptable
salts thereof, as described herein, that can be isolated and
characterized by methods known in the art, such as, thermogravimetric
analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder
X-ray diffraction (PXRD), Karl Fisher titration, high resolution X-ray
diffraction, and the like. There are several commercial entities that
provide quick and efficient services for identifying solvates and
hydrates on a routine basis. Example companies offering these services
include Wilmington PharmaTech (Wilmington, Del.), Avantium Technologies
(Amsterdam) and Aptuit (Greenwich, Conn.).

[0736] The invention will be described in greater detail by way of
specific examples. The following examples are offered for illustrative
purposes, and are not intended to limit the invention in any manner.
Those of skill in the art will readily recognize a variety of noncritical
parameters which can be changed or modified to yield essentially the same
results.

EXAMPLES

[0737] Illustrated syntheses of the present invention are shown in the
following examples. The following examples are provided to further define
the invention without, however, limiting the invention to the particulars
of these examples. The compounds and salts thereof described herein,
supra and infra, are named according to the CS ChemDraw Ultra Version
7.0.1, AutoNom version 2.2, or CS ChemDraw Ultra Version 9.0.7. In
certain instances common names are used and it is understood that these
common names would be recognized by those skilled in the art.

[0738] Chemical shifts of proton nuclear magnetic resonance ('H NMR)
spectra are given in parts per million (ppm) with the residual solvent
signal used as reference. NMR abbreviations are used as follows:
s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, bs=broad
singlet, dd=doublet of doublets.

[0740] To a 10 L jacketed reactor was added dry THF (2.4 L) and magnesium
turnings (81.0 g, 3.33 mol, 1.5 eq.) under N2. In a separate flask
FeCl3 (36 g, 0.22 mol, 0.1 eq.) was dissolved in THF (150 mL)
(caution, exothermic) under N2. This dark brown solution was allowed
to cool to ambient temperature and then added over 10 min to the reactor
content under N2 at an internal temperature of about 10° C.
TMEDA (402 mL) was added to this yellow/green mixture keeping the
internal temperature below about 20° C. (slightly exothermic). The
resulting rust brown mixture was stirred at ambient temperature for 1 h
under N2 then 1 h at 45° C. The reactor contents were allowed
to cool below about 20° C. and a mixture of
1-bromo-2-(trifluoromethyl)benzene (500 g, 2.22 mol) and
bromocyclopentane (397 g, 2.66 mol, 1.2 eq.) added dropwise under N2
at a rate as to maintain the internal temperature between about
25-30° C. After the addition, the reaction mixture was stirred at
about 25° C. under N2 overnight, allowed to cool to an
internal temperature of about 0° C. and quenched with 6 N HCl (2
L) at a rate as to maintain the internal temperature below about
15° C. (caution, exothermic). [Note: 1PC's after completing the
addition and stirring overnight were similar indicating that the reaction
may have been completed much sooner.] After the quench, hexane (3 L) was
added and the reactor contents were stirred at ambient temperature for 1
h. The phases were separated and the aqueous layer back extracted with
hexane (1 L). The combined organic layers were dried (Na2SO4),
slurried with silica (750 g) and filtered washing the solids with hexane
(1 L). The filtrate was concentrated under reduced pressure (100 torr at
37° C.) to give an amber oil (317 g, 97.3 Area % by HPLC, 87.7 wt
% by HPLC (contained residual hexane by NMR), corrected yield 58%) which
was used in the next step without further purification.

Preparation of 1-Cyclopentyl-2-(trifluoromethyl)benzene (Compound of
Formula (IIb)), two step process using 1-bromo-2-(trifluoromethyl)benzene

Step A: Preparation of 1-(2-(Trifluoromethyl)phenyl)cyclopentanol

[0742] A solution of 1-bromo-2-(trifluoromethyl)benzene (0.5 g, 2.222
mmol) in anhydrous THF (10 mL) was cooled to -78° C. (dry ice WA
bath) under argon atmosphere. BuLi (2.5 M in hexanes, 1.068 mL, 2.67
mmol) was added in drops with efficient stirring. The reaction mixture
was stirred at -78° C. for 40 min. A solution of cyclopentanone
(0.243 g, 2.89 mmol) in anhydrous THF (1.5 mL) was added slowly (in
drops) at -78° C. The reaction mixture was stirred at -78°
C. for 30 min, gradually brought to room temperature, and stirred for 1
h. The reaction mixture was cooled by an ice bath, quenched with water,
and acidified to pH 4-5 by addition of concentrated HCl. The solvent was
removed under reduced pressure. The residue was dissolved in methylene
chloride, washed with water (2 times), dried over Na2SO4,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel chromatography to give the title compound as an
oil (250 mg). LCMS m/z=213.1 [M-H2O+H].sup.+.

Preparation of 4-(Chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene
(Compound of Formula (IIc)), use of 1,3,5-trioxane and chlorosulfonic
acid

[0744] To a 5 L jacketed reactor concentrated sulphuric acid (718 mL) was
added and cooled to an internal temperature of about -10° C. under
N2. 1-Cyclopentyl-2-(trifluoromethyl)benzene (405 g, 89 wt %, 1.68
mol) was added to the reactor content at once. To the resulting dark
brown solution chlorosulfonic acid (225 mL, 3.37 mol, 2 eq.) was added
under N2 while maintaining the internal temperature below about
-10° C. (caution, HCl evolution). Then, 1,3,5-trioxane (606 g,
6.73 mol, 4 eq.) was added at such a rate as to maintain the temperature
below about -10° C. (caution, delayed exotherm: temperature rose
to 17° C. over 30 min, HCl evolution. Controlling the exotherm
minimizes the formation of the dimer (i.e.,
bis(4-cyclopentyl-3-(trifluoromethyl)-phenyl)methane). After the addition
and stirring at 0° C. for 1 h (IPC showed no more starting
material) under N2, the reaction mixture was slowly poured over ice
water (5 L) with stirring while maintaining the internal temperature
below 25° C. The reactor was rinsed with ice water (1.5 L) and the
combined aqueous layers extracted with hexane (3.6 L). The phases were
separated and the aqueous layer back extracted with hexane (3.6 L). The
combined organic layers were filtered through a pad of Celite® and
washed with saturated NaHCO3 (1.44 L) then water (1.44 L). The
organics were concentrated (30 torr at 30° C.) and the resulting
dark brown oil passed through a plug of silica eluting and washing with
hexane. The solvent was rotary evaporated (30 ton at 30° C.) to
afford the product (314 g, 81 wt % by NMR, corrected yield 58%) as a
yellow oil. A sample of the crude product was further purified by
distillation at 72° C. and 0.12 atm (91 ton) to yield the title
compound (98 wt % by HPLC) as a clear colorless oil. The distillation
residue contained mostly the dimer species and nearly all of the title
compound is recovered in the distillate.

Method 2

Preparation of 4-(Chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene
(Compound of Formula (IIc)), use of 1,3,5-trioxane and thionyl chloride

[0745] Sulfuric acid (1.606 L, 3.01 mol) was transferred into the 30 L
jacketed reaction vessel, fitted with a temperature probe, a mechanical
stirrer, nitrogen inlet and connected to a chiller/heater. The acid was
cooled to -4.5° C. and thionyl chloride (547 mL, 7.49 mol) was
added at -4.5° C. via an addition funnel. The reaction temperature
was maintained between -5 to -3.5° C. during addition. The mixture
was cooled to -6.5° C. and 1,3,5-trioxane (506 g, 5.621 mol) added
in four batches (126.5 g each batch) maintaining the reaction temperature
between -6.5 to -2° C. (addition of trioxane was exothermic). The
mixture was cooled to -5° C. and
1-cyclopentyl-2-(trifluoromethyl)benzene (802.8 g, 3.747 mol) was added
slowly via an addition funnel (controlled addition), the addition was
exothermic and the temperature was maintained exotherm between -5 to
-2.5° C. The reaction was held between -2.5 to +3.5° C. for
1.5 and at 5° C. for 30 min. The reaction mixture was gradually
warmed up to 15° C. and stirred overnight. Analysis of the
reaction sample by TLC (5% EtOAc-hexane)) showed only product. Analysis
by LC/MS showed the product and the slight presence of the dimer (i.e.,
bis(4-cyclopentyl-3-(trifluoromethyl)-phenyl)methane). The reaction
mixture was cooled to -2° C. and quenched with controlled addition
of water (11 L) and the temperature was maintained below 15° C.
during the aqueous quench (caution: very exothermic). The aqueous slurry
was extracted with MTBE (two times: 5L and 4 L respectively). The
combined MTBE layer was washed with satd. NaHCO3 (1×4L)
followed by brine (1 L) solution. The MTBE layer was finally washed with
water (2 L) and brine (2 L). The MTBE layer was dried (anhydrous
Na2SO4), filtered and the solvent removed under reduced
pressure to obtain the product as an oil, 913 g (crude weight). The crude
product was purified by vacuum distillation at 90-93° C./0.15 to
0.2 Ton to obtain the purified product as a very faint yellow oil, 788.4
g (80%); 1H NMR similar to previous experimental; HPLC purity,
98.37% (by peak area).

[0758] Cyclopentanone (4.00 kg), morpholine (4.16 kg) and cyclohexane
(7.96 kg) were charged to a 50-L glass-lined reactor equipped with
overhead agitation, jacket temperature control, a nitrogen inlet, and a
Dean-Stark trap. The reactor contents were heated to about 85° C.
to 95° C. for approximately 26 h so as to collect approximately
1.29 kg of water in the Dean-Stark trap. The reaction to form the enamine
(i.e., 4-cyclopentenylmorpholine, Compound of Formula (IIe) wherein
R1 and R2 together with the nitrogen atom form a morpholine
ring) is deemed complete when the morpholine amount by GC is verified to
be less than 3% by GC peak area.

[0759] The reactor contents were cooled to about 60° C. and ethyl
glyoxalate (Compound of Formula (IIf) wherein R3 is ethyl; 10.70 kg,
50% solution in toluene) was added to the mixture slowly so as to
maintain an internal temperature of ≦80° C. The reactor
contents were heated to about 85° C. to 95° C. for
approximately 26 hours so as to collect approximately 0.94 kg of water in
the Dean-Stark trap. The reaction to form the enamine ester was deemed
complete when the eneamine (i.e., 4-cyclopentenylmorpholine) amount by GC
was verified to be less than 0.5% by GC peak area. The
cyclohexane/toluene mixture was vacuum distilled at 41° C. and 4
mm of Hg to remove most of the cyclohexane (9.36 kg). Then, ethanol
(47.59 kg) was charged to the reactor, and the resulting solution was
vacuum distilled at 28.1° C. and 4 mm Hg to remove solvent (48.15
kg). Ethanol (6.32 kg) and water (8.00 kg) were charged to the reactor
and the reactor contents stirred at 25° C. The mixture was stirred
further for 16 h at about 0-5° C.

[0760] The product slurry was collected by filtration, washed with two
portions of aqueous ethanol (6.31 kg ethanol dissolved in 32.27 kg
water). The filter-cake was further washed with water (19.99 kg), dried
at 45° C. to 50° C. under vacuum for 71 h. The product,
ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate (4.84 kg, Compound of
Formula (IIg), wherein R3 is ethyl) was obtained in 42.8% yield and
99.6 Area % by HPLC.

Preparation of E/Z Ethyl
2-(7-(Benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate
(Compound of Formula (IIi), Wherein R3 is Ethyl, and R4,
R5, and R6 are each H)

Method 1

[0762] To a nitrogen-purged 5-L reactor was charged
(4-(benzyloxy)phenyl)hydrazine hydrochloride (538 g, 2.15 mol), ethyl
2-(2-morpholinocyclopent-2-enylidene)acetate (560 g, 2.36 mol, 1.1 eq;
Compound of Formula (IIg), wherein R3 is ethyl), ethanol (1.4 L) and
acetic acid (0.75 L). The internal temperature was raised to 60°
C. and the reaction was monitored by HPLC for the disappearance of
starting materials. TFA (1.2 eq, 294 g, 2.58 mol) was charged drop wise
while maintaining an internal temperature of 62.5°
C.±2.5° C. The reaction was monitored for completion by HPLC
and was considered complete when the imine intermediate was less than 4
Area %. The internal temperature was decreased to room temperature
(22° C.) and held for >12 hours to allow crystallization and
isomerization of the Z-isomer to the E-isomer. The reaction mixture was
cooled to 4° C.±2° C. and filtered. The filter cake was
rinsed with chilled ethanol (3×500 ml at 5° C.±3°
C.). The filter cake was rinsed with water (1×1.5 L, 1×500
mL, at 20±3° C.). The solids were dried under reduced pressure
(45±5° C., 19 in Hg.) to afford 297.8 g (40%) as a yellow
powder.

[0766] The E/Z mixture of ethyl
2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate (7.5
g, 21.59 mmol) and 10% Pd/C (50% wet; 1.13 g, 10.58 mmol) were taken up
in ethyl acetate (60 mL, 613 mmol). The suspension was degassed 3×
with N2 and followed with pre-activation of the catalyst with the
addition of formic acid (2.48 mL, 64.8 mmol). The mixture was allowed to
stir for 1-2 min. Triethylamine (9.03 mL, 64.8 mmol) was charged
portion-wise maintaining the temperature<35° C. Upon complete
addition of triethylamine, the mixture was stirred for about 5-10 minutes
followed with heating to 50° C. The reaction progression was
followed by HPLC to monitor the complete consumption of starting material
(i.e., E/Z mixture of ethyl
2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate) and
the debenzylated intermediate. Approximately after 4 h at 50° C.,
the solution was cooled to about 20° C., the Pd/C was removed via
vacuum filtration and rinsed with ethyl acetate (30 mL). To the filtrate
was added water (75 mL) and the biphasic mixture was partitioned. The
organics were washed with water (2×60 mL), concentrated under
vacuum with a bath temp of 40° C. to a minimum stir volume, chased
with ethyl acetate (1×37.5 mL) and further concentrated under
vacuum to a minimum stir volume. Ethyl acetate (11 mL) was charged to the
crude mixture and the resulting solution was heated to 60° C.
Heptanes (34 mL) were charged maintaining the internal temperature at
60° C. The solution was slowly cooled to 10° C. and held
for 30 min. The slurry was filtered, the filter cake rinsed with heptanes
(2×52.5 mL) and the solids dried in the vacuum oven set to
40° C. to afford the title compound (2.78 g, 74.5% yield) as light
beige solids.

[0768] To a 3-neck 250 mL round bottom flask was charged E/Z mixture of
ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetat-
e (15 g, 43.2 mmol) and purged with N2. 10% Pd/C (50% wet; 2.34 g,
22.02 mmol) was charged and the contents degassed 3× with N2
followed by addition of ethyl acetate (120 mL, 1226 mmol). The solution
was degassed 3× with N2 and followed by the pre-activation of
the catalyst with the addition of formic acid (4.97 mL, 130 mmol). The
mixture was allowed to stir for 1-2 minutes. Triethylamine (18.05 mL, 130
mmol) was charged drop-wise maintaining an internal temperature between
about 24° C. to 30° C. The reaction was held at 30°
C. for 1 h to allow for reaction completion. The reaction progression was
monitored by HPLC. Upon reaction completion, the solution was cooled to
20° C. and the catalyst Pd/C was removed via vacuum filtration and
rinsed with 30 mL of ethyl acetate. Water (90 mL) was charged to the
filtrate and the biphasic mixture was partitioned. The organics were
washed with water (2×90 mL), concentrated under vacuum in bath temp
40° C. to a minimum stir volume, chased with ethyl acetate
(1×30 mL) and further concentrated under vacuum to a minimum stir
volume. Ethyl acetate (22.5 mL) was charged to the crude and the
resulting solution was heated to 60° C. Heptanes (67.5 mL) were
charged maintaining the internal temperature at 60° C. whereupon
crystallization was initiated. The slurry was cooled to 40° C. and
aged for 1 h, further cooled to 5-10° C. and aged for 0.5 h. The
slurry was filtered, the filter cake rinsed with heptanes (2×60 mL)
and the solids dried in the vacuum oven set to 40° C. to afford
the title compound (8.86 g, 79% yield) as light beige solids.

[0775] DCM (305 mL) was transferred to a 1 L 3-necked round-bottomed flask
and cooled to -11° C. (internal) (ice acetone bath). BBr3
(72.0 mL, 761 mmol) was added to the DCM with stirring. A solution of
ethyl 2-(7-methoxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate
(41.62 g, 152 mmol) in DCM (145 mL) was added in drops maintaining the
internal temperature of about -5 to 0° C. After the addition the
reaction was stirred for 1 h below about 0° C. The reaction
mixture was slowly poured into mixture of ice (400 mL) and saturated
K2CO3 (400 mL) and stirred well (pH maintained at 9-7). The
organic layer was separated, washed with brine (1×100 mL), dried
over MgSO4, filtered and concentrated under reduced pressure. The
residual brown oil was purified by passing it through a pad of silica gel
to give the title compound (8.03 g). LCMS m/z=260.2.

[0776] Ethyl
2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (24.0 g,
1.0 eq) was charged into a 1 L, 3-neck round bottom flask set in a
heating mantel with a J-KEM controller. Cesium carbonate (39.2 g, 1.3 eq)
was charged into the flask. Acetonitrile (250 mL) was charged into the
flask and the reaction mixture was stirred with a magnetic stir bar.
4-(Chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (26.7 g, 1.1
eq) was charged slowly over 20 minutes while heating the reaction
mixture. The internal temperature at the beginning of the charge was
about 21° C. and the internal temperature at the end of the charge
was about 82° C. Reaction temperature was maintained at 78°
C. 1PC taken after 2.0 hours indicated 95% conversion to product by HPLC.
After 2.5 hours the reaction temperature was reduced from about
78° C. to about 54° C. over 33 minutes. 125 mL of
acetonitrile (5 vol) was heated to 50° C. in a 250 mL Ehrlenmeyer
flask. Celite® was placed in a glass sintered filter funnel and
acetonitrile used to wash and pack the filter aid. The acetonitrile wash
was discarded to waste. The packed Celite® was approximately 0.5
inches. The reaction mixture was cooled to about 54° C. and
filtered through the Celite® filter aid in the glass sintered filter
funnel and washed with the 125 mL acetonitrile heated to about 50°
C. The acetonitrile filtrate was stirred under nitrogen at ambient
temperature for 1.0 hour. The filtrate was concentrated under reduced
pressure at about 24° C. forming a thick slurry; 260 mL of
distillate was collected. 375 mL of methanol was used to transfer the
slurry into a 1 L round bottom flask. The slurry was stirred under
nitrogen at ambient temperature for 15.0 hours. The slurry was placed in
an ice/salt bath and stirred under nitrogen for 1.2 hours. 150 mL of
methanol was placed in an ice/salt bath. The solids were filtered in a
Whatman disposable filter cup at about -11° C. and washed with
chilled methanol (125 mL). The off-white solids were placed in a vacuum
oven set at about 29° C. for 22.5 hours to afford 35.7 g of ethyl
2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-
penta[b]indol-3-yl)acetate (Compound of Formula (IIk), wherein R3 is
ethyl), 79% yield with 99.57 Area % by HPLC.

[0779] In a 2 L, 3-necked, round-bottomed flask under nitrogen atmosphere
were placed ethyl
2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (55.85 g,
215 mmol), cesium carbonate (84.2 g, 258 mmol),
4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (68 g, 259
mmol) in DMA (670 mL). The mixture was stirred for 15 minutes at room
temperature and heated at 50° C. overnight. The mixture was cooled
down to room temperature and filtered. The filtrate was concentrated
under vacuum. Hexanes (400 mL) were added and the mixture was heated to
40° C. to give a dark solution. The solution was cooled down to
room temperature over the weekend. The mixture was concentrated in vacuo
and dried under vacuum to give the title compound (129.7 g). LCMS
m/z=486.2.

[0780] To a solution of rac-ethyl
2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-
penta[b]indol-3-yl)acetate (20.00 g, 41.19 mmol) in acetonitrile (185 ml)
in a 500 mL three-neck RBF equipped with magnetic stir bar, N2
inlet, thermocouple, and condenser was added potassium phosphate buffer
(15 ml, 1.0 M, pH=7.80) and followed by addition of lipase B, Candida
antarctica, immobilized recombinant from yeast (1.0 g, 5865 U/g, 5865 U).
The resultant yellow suspension was stirred at about 40° C. under
N2 for 16 hours. To the mixture, 1 M citric acid was added to adjust
the pH to 3.96 which was then filtered on a Whatman filter cup. The
solids were washed with ACN (3×15 mL). The combined filtrate and
washings were concentrated at about 30° C. under vacuum to give an
orange residue, which was partitioned between EtOAc (60 mL) and brine (60
mL). The layers were separated and the aqueous layer was extracted with
EtOAc (2×40 mL). The combined organic layers were washed with
H2O (2×80 mL), brine (2×80 mL), dried over
Na2SO4, decanted, and concentrated at 30° C. under
vacuum to give an orange oil, which was dried under vacuum at room
temperature overnight to give a light orange oil (22.203 g) containing
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid. The crude was assayed to be 41.41 wt %
(9.194 g) with 99.42% ee.

[0781] To the crude (21.837 g)
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid (41.41% w/w; 9.043 g, 19.77 mmol)
containing the (S)-isomer as the ester impurity in a 200 mL round bottom
flask was added IPA (150.72 mL). The mixture was heated at 60° C.
under N2 till the oily residue dissolved completely. The resultant
orange solution was heated at about 60° C. for 5 min. Seeds of
L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetate (362 mg) were added. The seeds were
suspended in the orange solution. A 2.27 M aqueous solution of L-arginine
(8.709 mL, 3.44 g, 19.77 mmol) pre-warmed to about 60° C. was
added into the mixture dropwise over 30 min. A light yellow precipitate
formed gradually during the addition. The suspension was stirred for
about an additional 30 min. The temperature of the suspension was allowed
to drop at about 0.4° C. per minute to room temperature. The
mixture was agitated occasionally at room temperature overnight. The
suspension was filtered and the cake was washed with IPA (3×6 mL)
and EtOAc (3×15 mL). The filter cake was dried at room temperature
under vacuum overnight to give L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetate as a white solid (11.631 g, 44.7%): HPLC
99.38 Area %, 99.6% ee. TGA, PXRD, PLM, SEM and DSC indicated the solid
as a non-solvated, crystalline compound with an average aggregates size
of 18.05 microns and a melting point of 202.69° C.

[0785] (R)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetra-
hydrocyclopenta[b]indol-3-yl)acetic acid (174.7 mg, 0.381 mmol) was
dissolved in IPA (1.57 mL) and L-arginine (66.4 mg, 0.381 mmol) was added
as a solution in water (263 μL). The homogeneous solution was warmed
to 40° C. After 15 min at this temperature, a precipitate had
formed. The reaction mixture was warmed to 70° C. causing the
precipitate to dissolve. The heat bath was turned off. A precipitate
began to form at 40° C. and the reaction mixture was allowed to
cool to about 28° C. before collecting the solids by filtration.
The solids were washed with 14% water in IPA to give the L-arginine salt
of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahyd-
rocyclopenta[b]indol-3-yl)acetic acid (130 mg).

[0787] To a 50 L three-neck round-bottom flask equipped with a mechanical
stirrer, thermocouple, and nitrogen inlet, was added dry THF (35 L) and
cooled to 0-5° C. To the flask was added Iron (III) chloride (2.7
kg, 0.15 eq) portion wise over 30-60 min. and stirred for 15-30 min.
resulting in a clear greenish solution. Under a nitrogen atmosphere in a
dry 100 gallon glass lined reactor was added THF (87.5 L) and magnesium
turnings (4.05 kg, 1.5 eq), and cooled to 0-5° C. To the THF and
magnesium mixture was added the solution of FeCl3 in THF at a rate
to maintain the internal temperature below 10° C. To the resulting
yellow/green mixture was added TMEDA (15.5 kg, 1.2 eq) at a rate to
maintain the internal temperature below 20° C. The resulting
reaction mixture was heated to 40-45° C. for 1 hour and a mixture
of 1 bromo-2-(trifluoromethyl)benzene (25 kg, 1.0 eq) and
bromocyclopentane (19.9 kg, 1.2 eq) was added to the reaction mixture at
a rate to maintain an internal temperature below 25° C. The
resulting reaction mixture was allowed to stir at room temperature
overnight and subsequently cooled to an internal temperature of
0-5° C. To the resulting mixture was added 6 N HCl (100 L, 1.5 h)
at such a rate as to maintain the internal temperature below 15°
C. (caution, very exothermic). After the quench, MTBE (200 L) was added
and the reactor contents was stirred for 30 min. The phases were
separated and the aqueous layer back extracted with MTBE (75 L). The
combined organic layers were washed with H2O (50 L), brine (50 L)
and dried (MgSO4). The mixture was filtered through an in-line (1
micron) filter cartridge followed by an additional in-line (0.45 micron)
filter cartridge into a clean dry reactor. The solvent was evaporated
under vacuum (jacket≦30° C.) and co-evaporated with
heptanes (2×25 L) to provide a viscous liquid. The viscous liquid
was dissolved in heptanes (100 L) and passed through a silica plug (25
kg). The silica plug was eluted with heptanes (TLC, Rf˜0.8,
silica gel, heptanes) and the fractions containing the product were
evaporated to provide the title compound as a yellow liquid, 11.7 kg
(49.2%), purity as determined by HPLC was 94.1%. 1H NMR conforms to
reference standard.

[0789] To a 100 gallon glass lined reactor equipped with a stirrer was
added concentrated sulphuric acid (48.6 L) and cooled to an internal
temperature between about -5 to -10° C. under an atmosphere of
N2. To the sulfuric acid was added thionyl chloride (26.99 kg, 2 eq)
at a rate to maintain the internal temperature below -5° C. To the
resulting mixture 1,3,5-trioxane (15.3 kg, 1.5 eq) was added portion wise
at a rate to maintain the internal temperature below -5° C. After
the addition of 1,3,5-trioxane, 1-cyclopentyl-2-(trifluoromethyl)benzene
(24.0 kg) was added drop wise over a period of approximately 2-3 hours.
The reaction mixture was stirred at 0° C. for approximately 3-4
hours, allowed to warm to room temperature overnight and subsequently
cooled to an internal temperature of 0-5° C. To the resulting
mixture was added water (316 L) drop wise over a period of approximately
5-6 hours (Note: Very exothermic). After the quench with water, the
resulting aqueous mixture was extracted with MTBE (243 L and 123 L). The
combined organics were washed with saturated NaHCO3 (100 L), brine
(100 L), water (100 L), brine (100 L), and dried (MgSO4). The
mixture was filtered through an in-line (1 micron) filter cartridge
followed by an additional in-line (0.45 micron) filter cartridge into a
clean dry reactor. The solvent was evaporated under vacuum
(jacket≦30° C.) and further evaporated under vacuum at
35-40° C. The resulting oil was distilled under high vacuum to
provide the title compound as a yellow liquid, 24.8 kg (83%), purity as
determined by HPLC was 99.47%. 1H NMR conforms to reference
standard.

[0791] Cyclopentanone (22.00 kg), morpholine (22.88 kg) and cyclohexane
(43.78 kg) were charged to a 400 L glass-lined reactor equipped with
overhead agitation, jacket temperature control, a nitrogen inlet, and a
Dean-Stark trap. The reactor contents were heated to about 85° C.
to 95° C. for approximately 26 h while removing water using the
Dean-Stark trap. The reaction to form the enamine (i.e.,
4-cyclopentenylmorpholine, Compound of Formula (IIe) wherein R1 and
R2 together with the nitrogen atom form a morpholine ring) is deemed
complete when the morpholine amount is verified to be 3% by GC peak area.

[0792] The reactor contents were cooled to about 60° C. and ethyl
glyoxalate (Compound of Formula (IIf) wherein R3 is ethyl; 58.74 kg,
50% solution in toluene) was added to the mixture slowly so as to
maintain an internal temperature of ≦80° C. The reactor
contents were heated to about 85° C. to 95° C. for at least
25 hours while removing water using the Dean-Stark trap. The reaction was
deemed complete when the eneamine (i.e., 4-cyclopentenylmorpholine)
amount by GC was verified to be less than 0.5% by GC peak area. The
cyclohexane/toluene mixture was distilled under vacuum, ethanol (261.80
kg) was charged to the reactor, and the resulting solution was again
distilled under vacuum. Ethanol (34.76 kg) and water 44.00 kg) were
charged to the reactor and the reactor contents stirred at 25° C.
The mixture was stirred further for 6 h at about 0-5° C.

[0793] The resulting product slurry was collected by filtration, washed
with aqueous ethanol (34.76 kg ethanol dissolved in 176.00 kg water). The
filter-cake was further washed with water (110.00 kg), dried initially at
approximately 36° C. for 1 hour under vacuum and subsequently at
approximately 50° C. under vacuum for 17 h. The title compound was
obtained as a tan solid (23.48 kg, 37.8% yield).

[0795] To a 400 L glass-lined reactor equipped with overhead agitation,
jacket temperature control, and a nitrogen inlet was added
(4-(benzyloxy)phenyl)hydrazine hydrochloride (21.08 kg, 1.000 mole
equiv.), ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate (22.02 kg,
1.104 mole equiv.), ethanol (51.2 kg, 2.429 mass equiv.), and acetic acid
(36.8 kg, 1.746 mass eq.). After the reactor contents are allowed to
stand for 10 minutes, agitation and then heating to 60° C. to
65° C. (60° C. target) was started. While stirring at that
temperature, samples of the reaction mixture were taken over intervals of
approximately 30 minutes and analyzed by HPLC for
(4-(benzyloxy)phenyl)hydrazine, ethyl
2-(2-morpholinocyclopent-2-enylidene)acetate, and hydrazone content. When
(4-(benzyloxy)phenyl)hydrazine HPLC % area was <1, TFA (11.6 kg, 101.7
mol, 1.200 mole equiv., 0.550 mass equiv.) was charged over approximately
1 hour while the stirred reaction mixture was maintained at 60°
C.±5° C. with reactor jacket cooling. As stirring at 60°
C. to 65° C. was continued, the hydrazone and imine content of the
reaction mixture was monitored by HPLC. After stirring at 60° C.
to 65° C. for at least 12 hours the imine content of the reaction
mixture was <5% area by HPLC, and the stirred reaction mixture was
cooled to 20° C. to 25° C. over approximately 3 hours.
Stirring was maintained at that temperature to allow isomerization of the
Z isomer to the desired E isomer. The E isomer crystallizes from the
reaction mixture. The Z isomer and E isomer % area content of the
reaction mixture was monitored by HPLC during this period of stirring at
20° C. to 25° C., which was continued until the Z-isomer
content of the reaction mixture was <15% area by HPLC.

[0796] The stirred reaction mixture was cooled (0° C. to 5°
C.) over at least 2 hours and then filtered. The reactor was charged with
ethanol (27.4 kg, 1.300 mass equiv.), which was stirred and chilled to
0° C. to 5° C. and then used in two approximately equal
portions to slurry-wash the product filter cake twice. The reactor was
charged with ethanol (13.8 kg, 0.655 mass equiv.), which was stirred and
chilled to 0° C. to 5° C. and then used to wash the product
filter cake by displacement. The reactor was charged with USP purified
water (100 kg, 4.744 mass equiv.), and the temperature was adjusted to
20° C. to 25° C. The USP purified water was then used in
three approximately equal portions to wash the product filter cake three
times, the first two by reslurrying and the third by displacement. The
reactor was charged with ethanol (16.4 kg, 0.778 mass equiv.), stirred
and chilled to 0° C. to 5° C., and then used to wash the
product filter cake by displacement. The washed product filter cake was
dried under full vacuum first with a jacket temperature of 35° C.
for 1 hour and then with a jacket temperature of 50° C. While
drying continues with a jacket temperature of 50° C., the product
solids are turned over every 1 hour to 3 hours, and product samples are
analyzed for loss on drying (LOD) every ≧4 hours. When LOD was
<1%, the product was cooled to <30° C. The yield of the
title compound was 13.06 kg (37.59 mol, 44.7%).

[0798] To a 200 liter Hastelloy reactor was added ethyl
2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate (E/Z
mixture, 12 kg), 10% Pd/C (50% wet with H2O; 1.80 kg) and ethyl
acetate (108 kg). The suspension was degassed 3× with N2 and
triethylamine (1.76 kg) was added. To the resulting mixture was added
formic acid (3.34 kg) while maintaining the internal temperature at below
35° C. The reaction progression was followed by HPLC to monitor
the complete consumption of starting material (i.e., E/Z mixture of ethyl
2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate) and
the debenzylated intermediate. After approximately 30 minutes an
additional amount of formic acid (0.50 kg) was added and the combined
peak area of ethyl
2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate and
the related debenzylated intermediate was determined to be <1% area by
HPLC. The reactor contents were filtered through a 1.2 μm cartridge
filter followed by an in-line 0.2 μm inline polishing filter. To the
filtrate was added water (60 kg) and the biphasic mixture was
partitioned. The organics were separated and concentrated under vacuum at
approximately 60° C.±5° C. to a minimum stir volume,
ethyl acetate (21.6 kg) was added and the mixture was further
concentrated under vacuum to a minimum stir volume. Once again ethyl
acetate (16.8 kg) was charged to the crude mixture and the resulting
solution was heated to approximately 60° C. Heptanes (37.2 kg)
were charged maintaining the internal temperature at 60° C. The
solution was slowly cooled to approximately 0 to 5° C. and
approximately 2-3 hr to facilitate crystallization. The slurry was
filtered, the filter cake was reslurried in heptanes (27.12 kg) and ethyl
acetate (7.08 kg). The resulting suspension was filtered and the solids
dried under vacuum at approximately 40±5° C. (until the loss on
drying (LOD) is <1%) to afford the title compound (6.23 kg, 70.3%
yield) as a solid.

[0800] To a 50 liter glass reactor containing ethyl
2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (2.000 kg,
1.000 equiv.) was added cesium carbonate (3.266 kg, 1.300 equiv.) and
acetonitrile (15.720 kg) under nitrogen. To the resulting mixture was
added 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (2.228
kg, 1.100 equiv.) over approximately one hour while maintaining the
stirred reactor contents at 40° C.±5° C. After the
addition of 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene the
reactor contents were heated to 65° C.±5° C. with
stirring until the concentration of ethyl
2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate in the
reaction mixture was less than 2.0% area by HPLC. The reaction mixture
was cooled to 50° C.±5° C. and filtered under nitrogen
through a fine filter cloth with suction to remove cesium salts (Note:
ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydr-
ocyclopenta[b]indol-3-yl)acetate may precipitate below 30° C.). The
filter cake was washed with fresh hot (50° C.±5° C.)
acetonitrile (5.658 kg divided in approximately three equal portions).
The filtrates were returned to the reactor. The combined filtrates were
concentrated by vacuum distillation with a jacket temperature of
60° C.±10° C. To the reactor was added ethyl alcohol
(3.156 kg) and once again concentrated with stirring by vacuum
distillation with a jacket temperature of 60° C.±10° C.
Once again, ethyl alcohol (3.156 kg) was added to the reactor and the
contents were concentrated by vacuum distillation with a jacket
temperature of 60° C.±10° C. to a reactor volume of
approximately 14 L. The stirred reactor contents were cooled to 0°
C. f 5° C. and the temperature maintained for 4 hours to
facilitate the crystallization of the product. The resulting slurry was
filtered. The filter cake was washed with cold 0° C.±5°
C. ethyl alcohol (2×3.156 kg). The filter cake was dried under
vacuum at 35° C.±5° C. until the weight loss over hour
was to provide 3.0943 kg (81.0% yield) of the title compound as a solid.

[0802] A 1.0 M buffer solution was prepared containing potassium phosphate
monobasic (29.1 g, 0.0335 equiv.) in USP purified water (213 g) and
potassium phosphate dibasic (368.2 g, 0.331 equiv.) in USP purified water
(2.107 g). To a 50 liter glass reactor was added ethyl
2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-
penta[b]indol-3-yl)acetate (3.094 kg, 1.000 equiv.), Lipase B, Candida
antarctica, immobilized (88.18 g, 293250 units/kg of ethyl ester starting
material) and acetonitrile (22.32 kg). To the stirred contents of the
reactor was added the previously prepared 1.0 M potassium phosphate
buffer. The resulting mixture was stirred under nitrogen at a temperature
of 40° C.±5° C. until the
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid concentration was ≧35% area as
determined by HPLC (Note: although the reaction usually is complete after
about 10 hours, the reaction mixture may be held at 40° C. t
5° C. overnight). The stirred reactor contents were cooled to
25° C. f 5° C. and the pH was adjusted to between 4 and 5
by addition of a solution of citric acid (278.5 g, 0.228 equiv.)
dissolved in USP purified water (1.454 kg). The reactor contents were
filtered to remove immobilized lipase and phosphate and citrate salts.
The reactor and solids were washed with acetonitrile (4.827 kg) and the
combined filtrates were added backed into the reactor. The stirred
reactor contents were concentrated to a volume of 1.0 L to 2.0 L by
vacuum distillation at a jacket temperature of 55° C. f 5°
C. To the reactor was added ethyl acetate (5.582 kg) and USP purified
water (6.188 kg). The contents were stirred at 20° C.±5°
C. for at least 10 minutes and a solution of sodium chloride (1 kg) in
USP purified water (1 kg) was added to facilitate phase separation. After
phase separation was complete, the lower aqueous layer was drained. A
solution of sodium chloride (5.569 kg) in USP purified water (12.38 kg)
was divided in two approximately equal portions and the ethyl acetate
phase was washed (2×). The ethyl acetate phase was transferred into
a carboy and the reactor was rinsed with ethyl acetate (838.5 g) and
added to the carboy containing the ethyl acetate phase. The reactor was
washed sequentially with USP purified water (12.38 kg), acetone (4.907
kg), and ethyl acetate (838.5 g) and the ethyl acetate mixture from the
carboy was transferred back to the reactor and concentrated with stirring
to a volume of 1 L to 2 L by vacuum distillation at a jacket temperature
of 55° C.±5° C. To the reactor was added 2-propanol
(14.67 kg) and after stirring the resulting mixture was concentrated to a
volume of 1 L to 2 L by vacuum distillation at a jacket temperature of
55° C.±5° C. To the reactor was added 2-propanol (7.333
kg) and heated with stirring at 60° C.±5° C. until the
contents dissolved. The stirred reactor contents were cooled to
20° C.±5° C. and filtered through a medium-porosity
fritted-glass filter to remove any inorganic solids to provide a
2-propanol solution containing 1.3188 kg of the title compound.

[0804] To a 50 liter glass reactor containing the 2-propanol solution
prepared in Step G of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid (1.3188 kg, 1.000 equiv.) was added an
additional amount of 2-propanol (6.3389 kg) to adjust the total volume to
approximately 16.7 L/kg of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid. The reactor contents were stirred and
heated to 60° C.±5° C. To the reactor was added seed
material (L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid, 26.4 g, 0.0145 equiv.). The reactor
contents were stirred for approximately 5 minutes at 60°
C.±5° C. and a solution of L-arginine (502.5 g, 1.000 equiv.)
in USP purified water (1.27 kg) preheated to 60° C.±5°
C. was added over approximately 1 hour while maintaining the stirred
reactor contents at 60° C.±5° C. The stirring of the
reactor contents at 60° C.±5° C. was maintained for
approximately 1 hour and then allowed to cool at an approximate rate of
0.2° C./min to 1.0° C./min. to a temperature of 25°
C.±5° C. Once at approximately 25° C. the contents of
the reactor were stirred for approximately 1 hour maintaining the
temperature of 25° C.±5° C. The resulting slurry was
filtered and the filter cake was washed with 2-propanol (6.2511 kg
divided in three approximately equal portions) and with ethyl acetate
(13.560 kg divided in six approximately equal portions. The filter cake
was dried under vacuum at 40° C.±5° C. (until the weight
loss over ≧1 hour is ≦2%) to provide 1.657 kg of the title
compound (32.9% yield) as a crystalline solid.

[0806] Five additional lots of the L-arg salt have been prepared using
substantially this same synthetic method as described above, the DSC
melting onset temperatures for a sample from each of the lots is as
follows: 203.96° C., 203.00° C., 203.11° C.,
203.79° C. and 203.97° C.; the TGA Weight Loss out to
˜110° C. for a sample from each of the lots is as follows:
0.04%, 0.04%, 0.03%, 0.10%, and 0.12%.

Example 9

Preparation of the Calcium salt of
(R)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid

[0807] Prior to use,
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid, was slurried in acetonitrile
overnight, filtered and dried to produce a crystalline form. To the
crystalline form (40 mg) was added acetonitrile (1 mL) and the mixture
was warmed to 60° C. The counterion was added by adding 20 μL
of calcium acetate solution (2 M) and 20 μL of water then seeding with
crystalline salt and allowing to slowly cool to room temperature. The
resulting solid was filtered and dried to give the calcium salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid as a white solid.

[0808] Animals: Male BALB/c mice (Charles River Laboratories, Wilmington,
Mass.) were housed four per cage and maintained in a humidity-controlled
(40 to 60%) and temperature-controlled (68 to 72° F.) facility on
a 12 h:12 h light/dark cycle (lights on at 6:30 am) with free access to
food (Harlan Teklad, Orange, Calif., Rodent Diet 8604) and water. Mice
were allowed one week of habituation to the animal facility before
testing.

[0809] PLL Assay: Mice were given a 1.00 mg/kg oral dose of the
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid or dosing vehicle (0.5% methylcellulose
in sterile water) in a total volume of 10 mL/kg. Peripheral blood samples
were collected at 5 hours post-dose. The mice were anesthetized with
isoflurane and blood was collected via cardiac puncture. A complete cell
count (CBC), including lymphocyte count, was obtained using a
CELL-DYN® 3700 (Abbott Laboratories, Abbott Park, Ill.) instrument.
Results are presented in FIG. 1, in which peripheral blood lymphocyte
(PBL) count is shown for the 5 hour group. Reduction of the PBL count by
the test compound in comparison with vehicle is indicative of the test
compound exhibiting activity or inducing peripheral lymphocyte lowering.
It is apparent from inspection of FIG. 1 that
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid exhibited activity for inducing PBL
lowering (lymphopenia) in the mouse.

B. Rat PLL Assay.

[0810] Animals: Male Sprague-Dawley rats (7 weeks of age at start of
study) (Charles River Laboratories) were housed two per cage and
maintained in a humidity-controlled (40-60%) and temperature-controlled
(68-72° F.) facility on a 12 h:12 h light/dark cycle (lights on at
6:30 am) with free access to food (Harlan Teklad, Orange, Calif., Rodent
Diet 8604) and water. Rats were allowed one week of habituation to the
animal facility before testing.

[0811] PLL Assay: Rats were given a 1.00 mg/kg oral dose of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid, or dosing vehicle (0.5%
methylcellulose in sterile water) in a total volume of 1.00 mL/kg.
Peripheral blood samples were collected at 5 hours post-dose. Blood was
collected via indwelling catheter. A complete cell count (CBC), including
lymphocyte count, was obtained using a CELL-DYN® 3700 (Abbott
Laboratories, Abbott Park, Ill.) instrument. Results are presented in
FIG. 2, in which peripheral blood lymphocyte (PBL) count is shown for the
5 hour group. Reduction of the PBL count by the test compound in
comparison with vehicle is indicative of the test compound exhibiting
activity or inducing peripheral lymphocyte lowering. It is apparent from
inspection of FIG. 2 that
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid exhibited activity for inducing PBL
lowering (lymphopenia) in the rat.

Example 11

The effect of
(R)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid in an arthritis rat model

[0812] Female Lewis rats were used in this study. Acclimated animals were
anesthetized with isoflurane and given the first collagen injection (day
0). On day 6, they were anesthetized again for the second collagen
injection. Collagen was prepared by making a 4 mg/mL solution in 0.01 N
acetic acid. Equal volumes of collagen and incomplete Freund's adjuvant
were emulsified by hand mixing until a bead of this material held its
form when placed in water. Each animal received 300 μL of the mixture
each time, spread over 3 subcutaneous sites on the back.

[0813] Treatment (p.o., q. d., 5 mL/kg dosing volume) began on day 0 and
continued through day 16 with vehicle or compounds given at 24 h
intervals. Rats were weighed on days 0, 3, 6 and 9 through 17 and caliper
measurements of the ankles taken on days 9 through 17. The compound,
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid, was dosed at 0.3, 1 and 3 mg/kg.
Results are presented in FIG. 3. It is apparent from inspection of FIG. 3
that (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrah-
ydrocyclopenta[b]indol-3-yl)acetic acid exhibited activity for reducing
mean ankle diameter in the rat.

[0814] A compound of the invention can be shown to have therapeutic
efficacy in multiple sclerosis by showing it to have therapeutic efficacy
in experimental autoimmune encephalomyelitis (EAE), an animal model for
multiple sclerosis. In certain exemplary well-established models, EAE is
induced in rodents by injection of myelin oligodendrocyte glycoprotein
(MOG) peptide, by injection of myelin basic protein (MBP) or by injection
of proteolipid protein (PLP) peptide.

A. MOG-Induced EAE in Mice.

[0815] Animals:

[0816] Female C57BL/6 mice (8 to 10 weeks of age at start of study)
(Jackson Laboratory, Bar Harbor, Me.) were housed four per cage and
maintained in a humidity-controlled (40-60%) and temperature-controlled
(68-72° F.) facility on a 12 h:12 h light/dark cycle (lights on at
6:30 am) with free access to food (Harlan Teklad, Orange, Calif., Rodent
Diet 8604) and water. Mice were allowed one week of habituation to the
animal facility before testing.

[0820] Severity of disease symptoms was scored as follows (in increasing
order of severity): 0=normal; 1=limp tail OR hind limb weakness; 2=limp
tail AND limb weakness/weakness of 2 or more limbs; 3=severe limb
weakness or single limb paralysis; 432 paralysis of 2 or more limbs;
5=death.

[0821] Drug Treatment:

[0822] Mice were dosed orally, with vehicle or
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid, once a day from day 3 until day 21.
Dosing volume is 5 mL/kg. The compound,
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid, was dosed at 0.3 mg/kg, 1 mg/kg and 3
mg/kg. Mice were weighed daily. Mice were monitored daily from day 7
onward for disease symptoms. After the last dose on day 21, disease
progression was monitored daily for 2 more weeks. Reduction of the
severity of disease symptoms by
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid in comparison with vehicle was
indicative of the test compound exhibiting therapeutic efficacy in EAE.
It is apparent from inspection of FIG. 4 that
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid exhibited activity in the mouse EAE
assay.

Example 13

Effects of Compounds on Cardiac Telemetry in the Rat

[0823] Animals: Male Sprague-Dawley rats (250-300 g at time of surgery)
were implanted by Charles River Laboratories (Wilmington, Mass.) with
cardiac transmitting devices (Data Sciences PhysioTel C50-PXT) into the
peritoneal space, with a pressure-sensing catheter inserted into the
descending aorta. Rats are allowed at least one week to recover. Rats
were housed in individual cages and maintained in a humidity-controlled
(30-70%) and temperature-controlled (20-22° C.) facility on a 12
h:12 h light/dark cycle (lights on at 7:00 am) with free access to food
(Harlan-Teklad, Orange, Calif., Rodent Diet 8604) and water. Rats were
allowed one week of habituation to the animal facility before testing.

[0824] Measurement of Cardiovascular Parameters:

[0825] The implanted transmitting devices transmitted continuous
measurements of blood pressure (systolic, diastolic, mean arterial,
pulse), heart rate, body temperature, and motor activity in freely moving
conscious animals. These data were transmitted via radiofrequency to a
computer which binned the data into min averages using DataSciences ART
software. Telemetry recording occurred over a 21-h period, starting at
noon and continuing until 9:00 am the following day. A maximum of eight
rats were tested at a time, and the same eight rats were utilized for all
treatment groups in a within-subject design.

[0826] Drug Treatment:

[0827] Rats were injected orally with vehicle (PEG400) and
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid at 1:00 pm. A full study (vehicle+3
doses) required four separate testing sessions, which occur on
Mondays-Tuesdays and Thursdays-Fridays. During each of the testing
sessions, the eight rats were divided into four treatment groups such
that each group comprised N=2 for any given session. Rats were re-tested
in subsequent testing sessions in a crossover design such that by the end
of the four sessions, all animals had received all treatments in a
pseudo-random order, and each group comprised N=8.

[0828] Exemplary Bradycardia Assay:

[0829] It was expressly contemplated that the rats could be used to show
that a compound of the invention had no or substantially no activity for
bradycardia. By way of illustration and not limitation, the rats were
administered vehicle (PEG 400) and
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid and heart rate was then measured over a
120 min period. Results are presented in FIG. 5. It is apparent from
inspection of FIG. 5 that no or substantially no reduction of heart rate
was exhibited in response to the treatment of rats with
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid in comparison with vehicle. No or
substantially no reduction of heart rate was indicative for
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid, thus exhibiting no or substantially no
activity for bradycardia.

Example 14

Powder X-Ray Diffraction (PXRD)

[0830] Powder X-ray Diffraction (PXRD) data were collected on an X'Pert
PRO MPD powder diffractometer (PANalytical, Inc.) with a Cu source set at
45 kV and 40 mA, a Ni-filter to remove Cu KO radiation, and an
X'Celerator detector. The instrument was calibrated by the vendor using a
silicon powder standard NIST #640c. The calibration was found to be
correct when it was tested with NIST #675 low-angle diffraction standard.
Samples were prepared for PXRD scanning by placing several milligrams of
gently ground compound onto a sample holder and smoothing as flat as
possible by pressing weigh paper down on the sample with a flat object.
The samples were analyzed using a spinning-sample stage. Scans cover the
range of 5 to 40° 2θ. A continuous scan mode is used with a
step size of 0.0167° 2θ. Diffraction data were viewed and
analyzed with the X'Pert Data Viewer Software, version 1.0a and X'Pert
HighScore Software, version 1.0b, FIG. 5 shows a powder X-ray diffraction
(PXRD) pattern for the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid (Compound of Formula (Ia)).

Example 15

Differential Scanning Calorimetry (DSC)

[0831] Differential Scanning calorimetry (DSC) was performed on a TA
instruments, Inc. DSC Q2000 at 10° C./min. from ˜25 to
˜210° C. The instrument was calibrated at this scan rate by
the vendor for temperature and energy using the melting point and
enthalpy of fusion of an indium standard. Samples were prepared by
piercing a sample-pan lid with a thumb tack or other sharp tool and
taring this lid along with a sample-pan bottom on a Mettler Toldeo MX5
balance. The sample was placed in the bottom of the tared sample pan. The
sample-pan lid fitted snuggly in the sample-pan bottom. The sample and
pan were reweighed to get the sample weight. Thermal events (onset
temperature, enthalpy of fusion, etc.) were calculated using the
Universal Analysis 2000 software, version 4.1D, Build 4.1.0.16, FIG. 6
shows a differential scanning calorimetry (DSC) thermogram for the
L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid (Compound of Formula (Ia)).

Example 16

Thermal Gravimetric Analysis (TGA)

[0832] Thermal Gravimetric Analysis (TGA) was performed on the TA
Instruments, Inc. TGA Q500. The instrument was calibrated by the vendor
at 10° C./min. for temperature using the curie point of a
ferromagnetic standard. The balance was calibrated with a standard
weight. Sample scans were performed at 10° C./min. from ˜25
to ˜250° C. Sample was placed into an open sample pan,
previously tared on the TGA balance. Thermal events such as weight-loss
were calculated using the Universal Analysis 2000 software, version 4.1D,
Build 4.1.0.16, FIG. 7 shows a thermogravimetric analysis (TGA)
thermogram for the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid (Compound of Formula (Ia)).

Example 17

Vapor Sorption Analysis

[0833] Hygroscopicity was measured using a dynamic moisture-sorption
analyzer, VTI Corporation, SGA-100. The sample was placed as-is in a
tared sample holder on the VTI balance. A drying step was run at
40° C. and 1% RH for 20 minutes. The isotherm conditions were
25° C. with steps of 20% RH from 10% RH up to 90% RH and back to
10% RH. Weight was checked every 5 minutes. Consecutive % weight change
of <0.01% or 2 hours, whichever occurred first, was required before
continuing to the next step, FIG. 8 shows a moisture sorption analysis
for the L-arginine salt of
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid (Compound of Formula (Ia)).

[0834] The compound
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroc-
yclopenta[b]indol-3-yl)acetic acid was shown to be an agonist of the S1P1
receptor (e.g., human S1P1 receptor) using the HTRF® assay for direct
cAMP measurement (Gabriel et al., Assay and Drug Development
Technologies, 1:291-303, 2003) and recombinant CHO-K1 cells stably
transfected with S1P1. CHO-K1 cells were obtained from ATCC®
(Manassas, Va.; Catalog #CCL-61). The compound was determined to be an
agonist of the S1P1 receptor and was detected in the HTRF® assay for
direct cAMP measurement as a compound which decreased cAMP concentration.
The HTRF® assay has been used to determine EC50 values for S1P1
receptor agonists.

[0835] Principle of the Assay:

[0836] HTRF® assay kit was purchased from Cisbio-US, Inc. (Bedford,
Mass.; Catalog #62AM4PEC). The HTRF® assay supported by the kit is a
competitive immunoassay between endogenous cAMP produced by the CHO-K1
cells and tracer cAMP labeled with the dye d2. The tracer binding is
visualized by a monoclonal anti-cAMP antibody labeled with Cryptate. The
specific signal (i.e., fluorescence resonance energy transfer, FRET) is
inversely proportional to the concentration of unlabeled cAMP in the
standard or sample.

[0837] Standard Curve:

[0838] The fluorescence ratio (665 nm/620 nm) of the standards (0.17 to
712 nM cAMP) included in the assay was calculated and used to generate a
cAMP standard curve according to the kit manufacturer's instructions. The
fluorescence ratio of the samples (test compound or compound buffer) was
calculated and used to deduce respective cAMP concentrations by reference
to the cAMP standard curve.

[0839] Setup of the Assay:

[0840] The HTRF® assay was carried out using a two-step protocol
essentially according to the kit manufacturer's instructions, in 20 μL
total volume per well in 384-well plate format (ProxiPlates; PerkinElmer,
Fremont, Calif.; catalog #6008280). To each of the experimental wells was
transferred 1500 recombinant CHO-K1 cells in 5 μL phosphate buffered
saline containing calcium chloride and magnesium chloride (PBS+;
Invitrogen, Carlsbad, Calif.; catalog #14040) supplemented with IBMX (250
μM) and rolipram (20 μM) (phosphodiesterase inhibitors;
Sigma-Aldrich, St. Louis, Mo.; catalog #15879 and catalog #R6520,
respectively), followed by test compound in 5 μL compound buffer (PBS+
supplemented with 104 NKH477 (water-soluble forskolin derivative;
SignaGen Laboratories, Gaithersburg, Md.; catalog #PKI-NKH477-010)) or 5
μL compound buffer. The plate was then incubated at room temperature
for 1 h. To each well was then added 5 μL cAMP-d2 conjugate in lysis
buffer and 5 μL Cryptate conjugate in lysis buffer according to the
kit manufacturer's instructions. The plate was then further incubated at
room temperature for 1 hour, after which the assay plate was read.

[0844] Citation of any reference throughout this application is not to be
construed as an admission that such reference is prior art to the present
application.

[0845] Those skilled in the art will recognize that various modifications,
additions, substitutions, and variations to the illustrative examples set
forth herein can be made without departing from the spirit of the
invention and are, therefore, considered within the scope of the
invention.

Patent applications by Antonio Garrido Montalban, San Diego, CA US

Patent applications by Ashwin M. Krishnan, San Diego, CA US

Patent applications by Daniel J. Buzard, San Diego, CA US

Patent applications by Dipanjan Sengupta, San Diego, CA US

Patent applications by John A. Demattei, Berthoud, CO US

Patent applications by Michael John Martinelli, San Diego, CA US

Patent applications by Stephen R. Johannsen, San Diego, CA US

Patent applications by Suzanne Michiko Sato, San Diego, CA US

Patent applications by Tawfik Gharbaoui, Escondido, CA US

Patent applications by You-An Ma, Poway, CA US

Patent applications by ARENA PHARMACEUTICALS, INC.

Patent applications in class Tricyclo ring system having the five-membered hetero ring as one of the cyclos

Patent applications in all subclasses Tricyclo ring system having the five-membered hetero ring as one of the cyclos